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Eosinophilia: secondary, clonal and idiopathic
Ayalew Tefferi,1 Mrinal M. Patnaik2 and Animesh Pardanani1
1Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, and 2Department of Medicine, University of
Minnesota, Minneapolis, MN, USA
Summary
Blood eosinophilia signifies either a cytokine-mediated reactive
phenomenon (secondary) or an integral phenotype of an
underlying haematological neoplasm (primary). Secondary
eosinophilia is usually associated with parasitosis in Third
World countries and allergic conditions in the West. Primary
eosinophilia is operationally classified as being clonal or
idiopathic, depending on the respective presence or absence of
a molecular, cytogenetic or histological evidence for a myeloid
malignancy. The current communication features a compre-
hensive clinical summary of both secondary and primary
eosinophilic disorders with emphasis on recent developments
in molecular pathogenesis and treatment.
Keywords: hypereosinophilic syndrome, FIP1L1-PDGFRA,
imatinib mesylate, diagnosis, treatment.
‘Theia yielded to Hyperion’s love and gave birth to great
Helios and bright Selene and Eos, who brings light to all
mortals of this earth and to the immortal gods who rule the
wide sky.’ – Hesiod, Theogony, 371–74
Hyperion and Theia were Titans in Greek mythology who
gave birth to three daughters: Helios, the goddess of the Sun;
Selene, the goddess of the Moon; and Eos, the goddess of
Dawn. Since time immemorial, Greek poets such as Homer
romanticised with the colours of dawn, whose glorious
reddish-crimson hues led to the naming of the first of the
synthetic aniline dyes, discovered by W.H. Perkins (1838–
1907) in 1856, as Eosin (Silverstein, 2005). Subsequently, the
great Paul Ehrlich (1854–1915), who won the 1908 Nobel Prize
for Physiology or Medicine, pioneered the use of chemical dyes
as selective biological stains for the study of human tissue
(Silverstein, 2005). Based on the specific affinities of certain
blood cells for either basophilic or acidophilic dyes, Ehrlich
defined and named several aniline-reactive leucocytes inclu-
ding the eosinophil (1879) and mast cells (1878) (Perkins,
1879; Crivellato et al, 2003). The selective action of aniline
dyes on cells and tissues suggested to Ehrlich the possibility of
creating ‘magic bullets’ that specifically target disease organ-
isms while sparing normal tissue. It is ironic that this very
concept has now been fully realised for platelet-derived growth
factor receptor (PDGFR)-rearranged eosinophilic disorders,
where treatment with Gleevec� (imatinib mesylate; STI571)
produces complete molecular remission with minimal toxicity
to normal tissue (Pardanani & Tefferi, 2004). Gleevec� is a
2-phenylaminopyrimidine tyrosine kinase inhibitor with
specific activity for the Abelson tyrosine kinase (ABL), PDGFR
and stem cell factor receptor (KIT).
Eosinophils are derived from haematopoietic stem cells that
are committed initially to the myeloid and subsequently to the
basophil–eosinophil lineage (Denburg et al, 1985). Cationic
proteins (major basic protein, eosinophilic cationic protein,
eosinophil-derived neurotoxin, eosinophil peroxidase), cytok-
ines (interleukins and tumour necrosis factor) and lipid
mediators (leucotrienes) constitute the content of the eosino-
philic granule and mediate parasite defence reaction, allergic
response, tissue inflammation and immune modulation (Ro-
thenberg & Hogan, 2005). Interleukin (IL)-3, IL-5 and
granulocyte monocyte-colony stimulating factor (GM-CSF)
are considered to be the major eosinophil growth and survival
factors and are coded by closely situated genes on chromosome
5q31–q33, a cytokine gene cluster that has also been linked to
familial eosinophilia (Rioux et al, 1998). Both types 1 and 2 T-
helper (Th1 and Th2) cells participate in early eosinophil
development (GM-CSF and IL-3) whereas Th2-derived IL-5
appears to be crucial in robust eosinophil proliferation (Wier-
enga et al, 1993). On the other hand, eosinophil chemotaxis and
tissue access are facilitated by C-C chemokines (eotaxin, CCR3,
PAF and RANTES) and endothelial adhesion molecules (inte-
grins and vascular cell adhesion molecules) (Garcia-Zepeda
et al, 1996; Gurish et al, 2002; Pope et al, 2005). In addition,
eotaxin has been shown to play a collaborative role, along with
IL-3 and IL-5, in early eosinophilopoiesis from murine embry-
onic stem cells (Hamaguchi-Tsuru et al, 2004). Eotaxin and its
receptor, CCR3, may also be involved in embryonic myelopoi-
esis, in general, and their differentiation into mast cells, in
particular (Quackenbush et al, 1998).
In health, the upper limits for peripheral blood eosinophil
percentage and absolute eosinophil count (AEC) do not exceed
5% and 0Æ5 · 109/l respectively (Brigden & Graydon, 1997).
Increased levels signify underlying disease and the degree of
Correspondence: Ayalew Tefferi, Division of Hematology, Department
of Internal Medicine, Mayo Clinic College of Medicine, 200 First Street
SW, Rochester, MN 55905, USA. E-mail: tefferi.ayalew@mayo.edu
review
ª 2006 The Authorsdoi:10.1111/j.1365-2141.2006.06038.x Journal Compilation ª 2006 Blackwell Publishing Ltd, British Journal of Haematology, 133, 468–492
eosinophilia is arbitrarily assigned as mild (AEC 0Æ5–1Æ5 · 109/
l), moderate (1Æ5–5 · 109/l) or severe (>5 · 109/l) (Brito-
Babapulle, 2003). Most instances of eosinophilia are acquired
although familial eosinophilia, an autosomal dominant disor-
der that is characterised by a stable eosinophil count and a
relatively benign clinical course, has rarely been described
(Klion et al, 2004a). From the early 20th century onwards, the
association of blood eosinophilia with parasitosis and allergic
diseases, both of which are IL-5 driven (Korenaga et al, 1991),
had been well recognised and the distinction between such
secondary cases and idiopathic eosinophilia was formalised in
1968 when Hardy and Anderson first introduced the term
hypereosinophilic syndrome (HES) (Hardy & Anderson, 1968).
At the same time, the occurrence of sometimes marked
eosinophilia in association with certain forms of leukaemia
and myeloproliferative disorders (MPD) did not go unnoticed
(Gray & Shaw, 1949; Spitzer & Garson, 1973; Ellman et al,
1979). Accordingly, acquired eosinophilia is currently classified
into secondary (cytokine-driven reactive phenomenon), clonal
(presence of a bone marrow histological, cytogenetic or
molecular marker of a myeloid malignancy) and idiopathic
(neither secondary nor clonal) categories (Table I). HES is a
subset of idiopathic eosinophilia that requires the presence of an
AEC of >1Æ5 · 109/l as well as evidence for target organ damage.
In addition to these features, the World Health Organization
(WHO) definition of HES requires the absence of aberrant
cytokine-secreting T-cell population (Bain et al, 2001).
Secondary eosinophilia
Infection
The most frequent cause of secondary eosinophilia worldwide
is tissue-invasive parasitosis that includes infections with
roundworms (nematodes), tapeworms (cestodes) and flukes
(trematodes). Table II features representative organisms in this
regard with their clinical presentation, geographical distribu-
tion and treatment drugs of choice (Zinkham, 1978; Hussain
et al, 1981; Milder et al, 1981; Maxwell et al, 1987; Evengard,
1990; Pozio et al, 1993; Arjona et al, 1995; Uchiyama et al,
1999). An elaborate travel history that includes specific
geography and exposure history to animals, insects, raw food
or untreated water is key for guiding pertinent laboratory
testing for suspected parasitosis. Infections other than those
caused by worms (helminths) are infrequently associated with
eosinophilia and involve certain (toxoplasmosis, isosporiasis,
Dientamoeba fragilis infection) but not other (Malaria, giardi-
asis, Entamoeba histolytica infection) protozoans, Borrelia
burgdorferi (a spirochete bacterium) and human immunode-
ficiency virus (HIV) (Grant & Klein, 1987; Junod, 1988;
Granter et al, 1996; Tietz et al, 1997; Windsor & Johnson,
1999). In general, parasites that are isolated in either the
intestinal lumen (tapeworms, ascaris) or an intact cyst
(Echinococcus granulosus, cysticercosis) do not cause blood
eosinophilia unless they are systemically introduced through
tissue invasion or cyst disruption (Windsor & Johnson, 1999;
Leder & Weller, 2000).
Repeated stool examinations are critical for the diagnosis of
parasite infestations that have intestinal phases in their life
cycles and should be done regardless of the presence or absence
of focal findings (Leder & Weller, 2000). In addition to stool,
ova and parasites are sought in duodenal aspirate (strongyloi-
diasis, ascariasis, ancylostomiasis, clonorchiasis, fascioliasis)
and sputum (strongyloidiasis, ascariasis, paragonimiasis,
ancylostomiasis, schistosomiasis) as clinically indicated. Other
laboratory investigations for suspected parasitosis include
serology for schistosomiasis, paragonimiasis, filariasis, stron-
gyloidiasis and toxocariasis. Furthermore, the presence of focal
findings warrants imaging studies, spinal fluid analysis, blood
smear examinations (filariasis), urine test (schistosomiasis,
filariasis) and tissue biopsy (muscle biopsy for trichinellosis,
liver or bladder biopsy for schistosomiasis) (Leder & Weller,
2000).
Table I. Causes of acquired eosinophilia.
(1) Secondary
(a) Infections (mostly helminthic)
(b) Drugs (anticonvulsants, antibiotics, sulpha drugs,
antirheumatics, allopurinol, food allergy)
(c) The pulmonary eosinophilias (see Table IV)
(d) Miscellaneous other causes of autoimmune/inflammatory/
toxic origin
(i) Eosinophilia-myalgia syndrome, toxic oil syndrome
(ii) Eosinophilic fasciitis (a.k.a. Schulman syndrome), Kimura
disease, Wells syndrome, Omenn syndrome
(iii) Connective tissue diseases (scleroderma, polyarteritis
nodosa, etc.)
(iv) Sarcoidosis, inflammatory bowel disease, chronic pancreatitis
(e) Malignancy (metastatic cancer, Hodgkin lymphoma)
(f) Endocrinopathies (Addison disease, growth factor
deficiency, etc.)
(2) Clonal
(a) Acute leukaemia (both myeloid and lymphoblastic)
(b) Chronic myeloid disorder
(i) Molecularly defined
(1) Bcr/Abl+ chronic myeloid leukaemia
(2) PDGFRA-rearranged eosinophilic disorder (SM-CEL)
(3) PDGFRB-rearranged eosinophilic disorder
(4) KIT-mutated systemic mastocytosis
(5) 8p11 syndrome
(ii) Clinicopathologically assigned
(1) Myelodysplastic syndrome
(2) Myeloproliferative disorder
(a) Classic myeloproliferative disorder (polycythaemia
vera, etc.)
(b) Atypical myeloproliferative disorder
(i) Chronic eosinophilic leukaemia
(ii) Systemic mastocytosis
(iii) Chronic myelomonocytic leukaemia
(iv) Unclassified myeloproliferative disorder
(3) Idiopathic including hypereosinophilic syndrome
Review
ª 2006 The AuthorsJournal Compilation ª 2006 Blackwell Publishing Ltd, British Journal of Haematology, 133, 468–492 469
Drugs
Different manifestations of drug-induced eosinophilia are
summarised in Table III and some, such as the DRESS
syndrome (drug rash with eosinophilia and systemic symp-
toms) are potentially fatal (Choquet-Kastylevsky et al, 1998,
2001; Britschgi et al, 2001; Carroll et al, 2001; Baraniuk &
Maibach, 2005, Ten et al, 1988; Roujeau, 2005). Drug-induced
skin lesions might or might not be accompanied by fever and
are markedly heterogeneous in their appearance; generalised
rash, Stevens–Johnson syndrome or toxic epidermal necrolysis
(Wolf et al, 2005). Differential diagnosis of a suspected drug
reaction includes infection (viral, bacterial, fungal), neoplastic
or paraneoplastic manifestation (e.g. lymphoma, leukaemia,
Sweet syndrome) and autoimmune/inflammatory conditions
(e.g. connective tissue disease, serum sickness, Kawasaki
disease). The systemic symptoms and signs of DRESS include
fever, extensive rash, lymphadenopathy, pneumonia, hepatitis,
arthritis and renal dysfunction. Other characteristic features
include delayed onset (2–6 weeks after the first drug use) and
the presence of atypical lymphocytosis. DRESS-associated
drugs include cephalosporins (Akcam et al, 2005), vancomycin
(Zuliani et al, 2005), nevirapine (Bourezane et al, 1998),
phenobarbital (Baruzzi et al, 2003), carbamazepine (Descamps
et al, 2001), phenytoin (Allam et al, 2004), minocycline
(Knowles et al, 1996), allopurinol (Markel, 2005), sulfasalazine
(Michel et al, 2005) and dapsone (Itha et al, 2003). Reactiva-
tion of human herpes virus 6 (HHV6) has been linked to
severe DRESS (Descamps et al, 2001).
The pulmonary eosinophilias
A few eosinophilic processes are characterised by pulmonary
lesions that are histologically composed of eosinophilic
infiltrates that might or might not be accompanied by
vasculitis, granulomas and microorganisms including fungi
Table II. Parasitosis associated with eosinophilia.
Disease/agent Clinical features Geographical distribution Treatment
Lymphatic filariasis (roundworm) Elephantiasis
Pulmonary tropical eosinophilia
Tropics, subtropics, Asia Diethylcarbamazine
Ivermectin
Loa loa filariasis (roundworm) Subconjunctival worms
Skin lesions, episodic angioedema
Western Africa Diethylcarbamazine
Onchocerca filariasis (roundworm) Skin nodules
Blindness
Africa, Latin America Ivermectin
Gnathostomiasis (roundworm) Cutaneous larva migrans
Visceral larva migrans (meningitis)
Asia, Mexico Albendazole
Ivermectin
Anisakiasis (roundworm) Acute abdominal pain Worldwide
Raw fish ingestion
Endoscopic removal of
larvae
Hookworm (roundworm)
Ancylostoma duodenale
Necator americanus
Iron deficiency anaemia Worldwide
Africa, Asia, the Americas
Australia, Middle East
Albendazole
Mebendazole
Pyrantel pamoate
Ascariasis (roundworm) Abdominal pain, oral expulsion
Intestinal or biliary obstruction
Loeffler syndrome (pneumonitis)
Worldwide
Tropics, Subtropics
Rural southeastern US
Albendazole
Mebendazole
Pyrantel pamoate
Strongyloidiasis (roundworm) Frequently asymptomatic
Abdominal pain, diarrhoea
Loeffler syndrome (pneumonitis)
Worldwide
Tropics, Subtropics
Rural South US
Ivermectin
Albendazole
Trichinosis (roundworm) Intestinal symptoms, myositis
myocarditis, conjunctivitis
Worldwide
Europe, US
Mebendazole
Albendazole
Toxocariasis (roundworm) Visceral and ocular larva migrans Worldwide Albendazole
Mebendazole
Angiostrongyliasis (roundworm) Eosinophilic meningitis Southeast Asia
Pacific Basin
No effective treatment
Paragonimiasis (lung fluke) Pneumonia, rusty sputum
Haemoptysis, skin lesions
Far East, Asia,
Latin America, Africa
Praziquantel
Fascioliasis (liver fluke) Hepatitis, hepatomegaly
Biliary obstruction
Worldwide
Raw watercress ingestion
Triclabendazole
Schistosomiasis
Haematobium Haematuria, bladder cancer Africa, Middle East Praziquantel
Mansoni Portal hypertension Latin America, Carribean Oxamniquine
Japonicum Portal hypertension Far East Praziquantel
Isosporiasis (coccidian parasite) Chronic diarrhoea Worldwide immunocompromised
hosts
Trimethoprim-
sulphamethoxazole
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ª 2006 The Authors470 Journal Compilation ª 2006 Blackwell Publishing Ltd, British Journal of Haematology, 133, 468–492
(Table IV) (Johkoh et al, 2000; Alberts, 2004; Grossi et al,
2004; Kalomenidis & Light, 2004; Khoo & Lim, 2004; Norman
et al, 2004; Shorr et al, 2004; Takafuji & Nakagawa, 2004;
Bargagli et al, 2005; Cottin & Cordier, 2005; Magnaval &
Berry, 2005). One example is allergic bronchopulmonary
aspergillosis (ABPA), which is a complication of long-standing
asthma or cystic fibrosis, where inhaled conidia from
Aspergillus fumigatus induce a host immune reaction that
consists of airway hyper-reactivity, pulmonary infiltrates with
fluctuating shadows and proximal bronchiectasias (Glimp &
Bayer, 1983; Kumar & Gaur, 2000; Soubani & Chandrasekar,
2002). Diagnosis is established by documenting an immediate
skin reaction to aspergillus antigens as well as increased levels
of A. fumigatus-specific IgG and IgE immunoglobulins and
increased total serum IgE level. Treatment consists of systemic
steroids and azoles (Salez et al, 1999). ABPA can sometimes
progress into a necrotising pneumonia (bronchocentric gra-
nulomatosis) that can also occur in the absence of ABPA
(Yousem, 1997).
Churg–Strauss Syndrome (CSS) is a systemic vasculitis that
involves small and medium vessel arteries and is characteris-
tically accompanied by asthma and blood eosinophilia (Abril
et al, 2003). In addition, many patients manifest rhinosinusitis,
nasal polyposis, mononeuritis multiplex and palpable purpura.
Less frequently encountered complications included pericar-
ditis, myocardial disease and renal failure. Treatment for CSS
includes corticosteroids and other immunosuppressive drugs.
Approximately 50% of CSS patients display circulating anti-
Table III. Drug-induced eosinophilic syndromes.
Manifestation Drugs
Generalised rash with or without fever Any drug is a possibility
Mostly seen with antibiotics
Interstitial nephritis with eosinophiluria Antibiotics, gold compounds, allopurinol
Pulmonary infiltrates Nitrofurantoin, minocycline, naproxen, penicillins, phenylbutazone,
sulindac, piroxicam, sulphonamides, nimesulide, tolfenamic acid
Pleuropulmonary manifestations Dantrolene sodium, bleomycin, methotrexate
Hepatitis Phenothiazines, penicillins, tolbutamide, allopurinol, methotrexate, fluoroquinolones
Leucocytoclastic vasculitis Allopurinol, phenytoin
Chronic rhinosinusitis with nasal polyposis and asthma Aspirin
Eosinophilia-myalgia syndrome l-tryptophan
DRESS syndrome (drug rash with eosinophilia
and systemic symptoms)
Carbamazepine, allopurinol, antibiotics, etc.
Table IV. The pulmonary eosinophilic syndromes.
Diagnosis Peripheral eosinophilia Radiology BAL/biopsy findings Systemic features
Chronic IEP Marked Peripheral opacities
Migratory infiltrates
Marked eosinophilia Non-specific, cough
Weight loss
Acute IEP Mild to absent Bilateral infiltrates
Pleural effusions
Marked eosinophilia ARDS
Recent-onset smoking
Churg–Strauss syndrome Marked Non-specific
Migratory infiltrates
Sometimes normal
Eosinophils
Vasculitis
Granulomas
Asthma, rhinosinusitis,
peripheral neuropathy
Cardiac and renal disease
Palpable purpura
Hypereosinophilic syndrome Marked Interstitial infiltrates
Pulmonary nodules
Pleural effusions
Eosinophils Cardiomyopathy
Hepatosplenomegaly
CNS vasculitis
Tropical pulmonary
eosinophilia (microfilariae)
Marked Bilateral opacities Eosinophils Fever, cough,
hyper-reactive airways
ABPA Moderate Mucus plugs
Centrilobular nodules
Proximal bronchiectasis
Eosinophils
Fungal hyphae
Allergic mucin
Asthma, Rhinosinusitis
Cystic fibrosis
Drug induced Mild Alveolar infiltrates
Pleural effusions
Eosinophils Fever, rash
Radiation induced Mild to moderate Unilateral infiltrates Eosinophils Fever, cough, dyspnoea
ARDS, acute respiratory distress syndrome; BAL, bronchoalveolar lavage; IEP, idiopathic eosinophilic pneumonia; ABPA, allergic bronchopulmonary
aspergillosis; CNS, central nervous system.
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ª 2006 The AuthorsJournal Compilation ª 2006 Blackwell Publishing Ltd, British Journal of Haematology, 133, 468–492 471
bodies to neutrophil cytoplasmic enzymes. Differential diag-
nosis in this instance includes Wegener granulomatosis and
microscopic polyangiitis. Other forms of pulmonary vasculitic
syndromes include giant cell arteritis, Takayasu arteritis and
those associated with connective tissue disorders, such as
polyarteritis nodosa, scleroderma, systemic lupus erythemato-
sus and polymyositis.
Certain pulmonary eosinophilic syndromes are operation-
ally classified as being idiopathic and include simple
pulmonary eosinophilia (a.k.a. Loffler pneumonia) (Loffler,
1932) and acute or chronic eosinophilic pneumonia (Table -
IV). Simple pulmonary eosinophilia is a self-limiting syn-
drome with fluctuating pulmonary infiltrates and blood
eosinophilia. Most such cases are currently linked to drug
reactions or parasite infections. Acute idiopathic eosinophilic
pneumonia (acute IEP) is a rare disorder that presents with a
corticosteroid-responsive acute respiratory distress syndrome
(ARDS) that is associated with marked bronchoalveolar
lavage (BAL) eosinophilia and might represent an unusual
host reaction to recent-onset smoking, drugs, infections or
inhaled toxins or dust (Shorr et al, 2004). Chronic IEP is also
rare, usually occurring in atopic women, and is characterised
by peripheral pulmonary infiltrates (Marchand et al, 1998).
Approximately 50% of patients have a history of asthma and
the clinical phenotype includes chronic cough, malaise and
weight loss. Chronic IEP responds well to systemic cortico-
steroid therapy but relapses are inevitable (Marchand et al,
1998).
Other miscellaneous causes of secondary eosinophilia
In October 1989, a group of physicians from New Mexico
reported a group of patients, taking nutritional supplements
containing l-tryptophan, with unusual visceral manifestations,
accompanied by peripheral eosinophilia (Das et al, 2004). The
patients manifested weakness, myalgia, arthralgia, rash, oral
ulcers, alopecia, sclerodermiform skin changes and increased
serum levels of muscle enzymes. This ‘eosinophilia-myalgia
syndrome’ was subsequently reported in several hundred cases
and associated with an increased risk of death (Sullivan et al,
1996). Similarly, in 1981, an outbreak of a deadly disease (toxic
oil syndrome) appeared in Spain and was clinically character-
ised by severe myalgia, marked peripheral eosinophilia and
pulmonary infiltrates (Diggle, 2001; Posada de la Paz et al,
2001; Sanchez-Porro Valades et al, 2003). Of the approxi-
mately 20 000 people affected, over 2500 deaths had occurred
by December 1995 and epidemiological observations suggested
a link with ingestion of adulterated rapeseed oil (Sanchez-
Porro Valades et al, 2003).
Eosinophilic fasciitis (Schulman syndrome) is a scleroder-
ma-like illness that was first described in 1974 and differen-
tiated from scleroderma by the absence of Raynaud
phenomenon and visceral involvement (Shulman, 1975; Mori
et al, 2002). The disease is common in young adult males and
the involved skin appears shiny and erythematous and
subsequently becomes taut and woody with subsequent joint
contractures. The pathogenesis of the disease is unknown and
corticosteroids are used for treatment. Kimura disease is
another rare chronic inflammatory disease that has a predi-
lection for young males (Chen et al, 2004a). Clinical features
include subcutaneous masses in the head and neck region
associated with regional lymphadenopathy. Histological fea-
tures include follicular hyperplasia, eosinophilic infiltrates and
proliferation of postcapillary venules (Chen et al, 2004a).
Wells syndrome is characterised by oedematous erythematous
plaques that are pruritic and resolve promptly with systemic
corticosteroid therapy (Falagas & Vergidis, 2005). In contrast,
Omenn syndrome is a form of severe combined immunode-
ficiency associated with high mortality. The disease affects
infants and is characterised by erythematous rash, hepatosple-
nomegaly, lymphadenopathy, recurrent infections and alopecia
(Aleman et al, 2001). Outcome is fatal unless haematopoietic
stem cell transplantation is performed.
Connective tissue/autoimmune diseases, especially systemic
lupus erythematosus (Thomeer et al, 1999), polyarteritis
nodosa (Kirkland et al, 1997) and scleroderma (Fleischmajer
et al, 1978), as well as sarcoidosis (Renston et al, 2000), can be
associated with mild eosinophilia. Other eosinophilia-associ-
ated chronic inflammatory conditions include inflammatory
bowel disease (Benfield & Asquith, 1986) and chronic
pancreatitis (Tokoo et al, 1992). The mechanism in the former
instance might involve eotaxin-mediated chemotaxis (Garcia-
Zepeda et al, 1996). The gastrointestinal system is a target
organ for many eosinophilic disorders whereas organ-specific
eosinophilic gastroenteritis might occur without associated
blood eosinophilia (Khan, 2005). Finally, paraneoplastic eosi-
nophilia is a well-known phenomenon in the setting of both
metastatic cancer and lymphomas (Sataline & Mobley, 1967;
Miller et al, 1977; Lowe & Fletcher, 1984; Balducci et al, 1989;
Di Biagio et al, 1996; Scales & McMichael, 2001; Anagnostop-
oulos et al, 2005). On the other hand, the association of
eosinophilia with either growth hormone or adrenal insuffi-
ciency is much less recognised (Spry, 1976; Kawada et al,
2001).
Clonal eosinophilia
The diagnosis of clonal eosinophilia requires the demonstra-
tion of either a cytogenetic/molecular marker of clonality or
bone marrow histological features that are consistent with an
otherwise classified myeloid malignancy. Examples of myeloid
disorders that might be accompanied by clonal eosinophilia
include both acute myeloid (AML) (Sanada et al, 1989) and
lymphoblastic (ALL) (Blatt et al, 1974) leukaemias, chronic
myeloid leukaemia (CML) (Keung et al, 2002), myelodysplas-
tic syndrome (MDS) (Kuroda et al, 2000) and MPD (Bain,
2003).
Peripheral blood and bone marrow histological clues for
clonal eosinophilia include macrocytosis, monocytosis, left
shift granulocytosis, presence of circulating blasts, thrombo-
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ª 2006 The Authors472 Journal Compilation ª 2006 Blackwell Publishing Ltd, British Journal of Haematology, 133, 468–492
cytosis, multilineage myeloproliferation, dyshaematopoiesis
and reticulin fibrosis. However, bone marrow histological
features can be subtle and the morphological distinction
between clonal eosinophilia and idiopathic eosinophilia
(including HES) is not always precise. In addition, intense
bone marrow eosinophilia might make it difficult to identify
neoplastic population of monocytes and mast cells. Therefore
immunohistochemical stains for tryptase and mast cell
immunophenotyping should accompany bone marrow exam-
ination in patients with an eosinophilic disorder before
assigning a diagnosis of idiopathic eosinophilia. On the other
hand, the detection of a clonal cytogenetic abnormality
confirms the diagnosis of clonal eosinophilia regardless of
how the bone marrow histology is interpreted. Furthermore,
current evaluation of suspected HES mandates molecular
investigation with either reverse transcription polymerase
chain reaction (RT-PCR) or fluorescent in situ hybridisation
(FISH) to exclude the possibility of the Gleevec�-sensitive,
karyotypically occult Fip 1-like-1 (FIP1L1)/PDGFRA-positive
eosinophilic disorder (Cools et al, 2003).
Molecular pathogenesis of clonal eosinophilia
Cytogenetic abnormalities in eosinophilic disorders are mostly
non-specific but in certain instances have helped identify
disease-causing mutations (Table V). Recently, recurrent
molecular abnormalities have been identified in eosinophilia-
associated MPD that have advanced our understanding of the
molecular pathophysiology of these disorders and which
increasingly support the development and use of a molecular
classification for these heterogenous disorders. Excluding the
molecularly well-characterised subtypes of AML, such as
French–American–British (FAB) subtypes M4eo and M2 that
exhibit eosinophilia, the chronic MPDs with associated
eosinophilia are largely linked to constitutively active cellular
tyrosine kinases, which drive the clonal cell proliferation. The
clinical significance of the prospective identification of such
mutant kinases is their susceptibility to molecularly targeted
small-molecule inhibitors, such as Gleevec�, which frequently
constitute a very effective treatment for these patients. Despite
the identification of mutant tyrosine kinases, many questions
regarding their role(s) in clonal eosinophilias remain unan-
swered to varying degrees (as illustrated below) – these pertain,
for instance, to the varied genotype–phenotype association(s)
and variable lineage distribution of specific molecular abnor-
malities, and to the role of additional molecular lesions and/or
heritable genetic polymorphisms that influence the disease
phenotype. Nevertheless, there is a remarkable association
between activating mutations of certain receptor tyrosine
kinases (e.g. PDGFR-a and -b) and eosinophilia-associated
MPD. One possible explanation for this might relate to the
common signalling pathways that such mutant kinases share
with IL-5 and other eosinophilopoietic cytokines (Eriksson
et al, 1992; Adachi & Alam, 1998; D’Andrea & Gonda, 2000;
Paukku et al, 2000). However, a recent study has suggested a
persistent role for IL-5 in the link between certain PDGFR
mutations and eosinophilia, thus reflecting the complexity of
the subject matter and the need for additional studies (Yamada
et al, 2006).
PDGFRA-rearranged eosinophilic disorders
Cytogenetically apparent: BCR-PDGFRA – t(4; 22)(q12;
q11). The first report of a chromosomal rearrangement t(4;
22)(q12; q11) targeting platelet-derived growth factor
receptor (PDGFR)-a (PDGFRA) pre-dated Gleevec� use
(Baxter et al, 2002). Molecular studies on two patients
presenting with atypical CML with associated eosinophilia
(one patient had extra-medullary T-lymphoblastic lymphoma
concurrently at diagnosis) revealed an in-frame breakpoint
cluster region (BCR) (breakpoints in intron 7 and exon 12)-
to-PDGFRA (breakpoints in exon 12) fusion mRNA.
Subsequently, Trempat et al (2003) described a case with
atypical CML evolving into pre-B ALL, with the BCR (exon
1)-to-PDGFRA (exon 13) fusion, who achieved a complete
haematological remission with Gleevec� treatment. Finally,
Safley et al (2004) reported a case with atypical CML and
eosinophilia, with the BCR (exon 17)-to-PDGFRA (exon 12)
fusion, who also responded to Gleevec�. All cases exhibited
the t(4; 22)(q12; q11) cytogenetic abnormality, and the
PDGFRA breakpoints were noted to be tightly clustered in
the juxtamembrane (JM) region, pointing to a key regulatory
(auto-inhibitory) role for this domain. Similar targeting of
the JM domain is also seen in the other PDGFRA-mediated
diseases, namely HES with FIP1L1-PDGFRA (Cools et al,
2003) (see below) and gastrointestinal stromal tumours
(Heinrich et al, 2003). Another study (Ketterling et al,
2004), screened 29 047 archived abnormal bone marrow
karyotypes and found 11 cases with a breakpoint involving
PDGFRA (Ketterling et al, 2004). Three cases implicate novel
translocation partners (1q44, 3q25 and 17q23) that have not
been cloned as of yet.
Cytogenetically occult: FIP1L1-PDGFRA. Following the
remarkable success of Gleevec� at a relatively low-dose
(�100 mg/day) in the treatment of HES [summarised in
(Pardanani & Tefferi, 2004; Gotlib, 2005)], a concerted multi-
institutional effort identified the FIP1L1-PDGFRA tyrosine
kinase as the molecular target for imatinib in a subset of HES
patients (Cools et al, 2003). Cloning of the FIP1L1-PDGFRA
fusion gene identified a novel molecular mechanism for
generating this constitutively active fusion tyrosine kinase,
wherein a c. 800 kb interstitial deletion within 4q12 fuses the 5¢portion of FIP1L1 to the 3¢ portion of PDGFRA (Cools et al,
2003). Molecular studies show that the breakpoint in FIP1L1 is
relatively promiscuous, while the PDGFRA breakpoint is
restricted to exon 12 that encodes part of the protein–
protein interaction module with two fully conserved
tryptophans (WW domain)-containing JM region (Cools
et al, 2003; Roche-Lestienne et al, 2005). Given the known
Review
ª 2006 The AuthorsJournal Compilation ª 2006 Blackwell Publishing Ltd, British Journal of Haematology, 133, 468–492 473
Table V. Cytogenetic anomalies reported in association with clonal eosinophilic disorders.
Chromosome
affected Karyotype Molecular phenotype
Clinicopathological
presentation References
1 t (1; 4) (q44:q12)
+1,dic (1; 7)(p10:q10)
1,der (1; 7)(q10; p10)
t (1; 5) (q21; q33)
t (1; 5) (q21; q31)
t (1; 5) (q21; q33)
t (1; 3; 5) (p36; p21; q33)
t (1; 5) (q23; p14)
Trisomy 1
PDGFRA-FIPILI rearrangement
Abnormality of PDGFRB
C-kit mutations
HES
Atypical CML
CMPD
CMPD
CMML
AML Eo
MDS
Cools et al (2003)
Forrest et al (1998)
Park et al (2004)
Baxter et al (2003)
Baxter et al (2003)
Baxter et al (2003)
Baxter et al (2003)
Zermati et al (2003)
Harrington et al (1988)
2 t (2; 4) (p24; q12)
t (2; 12; 5) (q37; q22; q33)
N-MYC-PDGFRA
PDGFRB mutation
HES
MDS
Musto et al (2004)
Musto et al (2004)
3 t (3; 4) (p13; q12)
t (3; 5) (p21; q31)
t (3; 5) (p13; q13)
HES
Atypical CML
HES/CEL
Myint et al (1995)
Baxter et al (2003)
Shanske et al (1996)
4 t (4; 7) (q11; q32)
t (4; 7) (q11; p13)
t (4; 16) (q11/12; p13)
del 4q12
t(4; 22) (q12; q11)
FIPILI-PDGFRA
BCR-PDGFRA
Atypical CML
MPD
Atypical CML
HES
Atypical CML
Duell et al (1997)
Schoffski et al (2000)
Hild & Fonatsch, 1990)
Gotlib, 2005; Roche-Lestienne
et al (2005)
Baxter et al (2002)
5 t (5; 9) (q11; q34)
t (5; 11) (p15; q13)
t(5; 14) (q33; q24)
t (5; 17) (q33; p11)
t (5; 15) (q33; q22)
t (5; 12) (q33; p13)
t (5; 14) (q33; q32)
t(5; 7) (q33; q11Æ2)t (5; 10) (q33; q11Æ2)t (5; 17) (q33; p13)
t (5; 14) (q33; q32)
t(5; 16) (q33; q22)
ABL-TK
NIN-PDGFRB
HCMOGT-1 PDGFRB
TP53BP1-PDGFRB
TEL (ETV6)-PDGFRB
CEV14-PDGFRB
HIP1-PDGFB
H4-PDGFRB
RAB5-PDGFRB
MPD
CEL
Atypical CML
JMML
Atypical CML
CMML
AML after clonal evolution
CML
Atypical CML
CMML
CMPD
AML Eo
Bakhshi et al (2003)
Yoo et al (1984)
Vizmanos et al (2004a)
Morerio et al (2004)
Grand et al (2004a)
Golub et al (1994)
Abe et al (1997)
Ross et al (1998)
Kulkarni et al (2000)
Magnusson et al (2001)
Levine et al (2005)
Bhambhani et al (1986)
6 t (6; 11) (q27; q23)
del (6) (q24)
t (6; 8) (p12; q12) FOP-FGFRI
HES/CEL
EMS
Suzuki et al (2001)
Gotlib (2005)
Popovici et al (1999)
7 t (7; 12) (p11; q11)
)7Monosomy 7
HES
MPD
AML Eo
da Silva et al (1988)
Humphrey et al (1981)
Song & Park (1987)
8 t (8; 9) (p22; p23)
t (8; 9) (p21; p24)
Trisomy 8
+ 8 p23
+I (8p)
+8; +9
+8; + 21
t (8; 13) (p12; q12)
t (8; 9) (p12; q33)
t (8; 22) (p11; q11)
t (8; 17) (p11; q25)
t (8; 19) (p12; q13Æ3)
FIPILI-PDGFRA
ZNF198-FGFR1
CEP110-FGFR1
BCR-FGFR1
FGFR1
HERVK-FGFR1
CEL
HES
CEL
CEL
HES
CEL
CEL
EMS
EMS
EMS
SM
EMS
Vandenberghe et al (2004)
Weinfeld et al (1977)
Kook et al (2002)
Egesten et al (1997)
Mori et al (1986)
Kueck et al (1991)
Popovici et al (1998)
Guasch et al (2000)
Demiroglu et al (2001)
Sohal et al (2001)
Guasch et al (2003)
9 Ins (9; 4) (934; q12q31) HES Schoch et al (2002)
Review
ª 2006 The Authors474 Journal Compilation ª 2006 Blackwell Publishing Ltd, British Journal of Haematology, 133, 468–492
auto-inhibitory role of the JM region for other receptor
tyrosine kinases including EPHB2 (Wybenga-Groot et al,
2001), FLT3 (Gilliland & Griffin, 2002) and KIT (Chan et al,
2003), disruption of this domain is probably the primary
mechanism for FIP1L1-PDGFRA activation.
Since its original description (Cools et al, 2003), other
studies have begun to clarify the prevalence and clinicopath-
ological associations of the FIP1L1-PDGFRA mutation (sum-
marised in Table VI). Our experience suggests that in
unselected cases of eosinophilia, prevalence of the mutation
is quite low (c. 4%) (Pardanani et al, 2005), but this remains to
be confirmed in a multi-institutional setting. Prevalence of the
mutation is higher in cohorts that satisfy World Health
Organization (WHO) criteria (Bain et al, 2001) for idiopathic
HES (12–88%), and particularly for the subgroup with
myeloproliferative features, including marrow fibrosis, an
elevated serum tryptase level and increased numbers of
neoplastic mast cells in the bone marrow. These patients have
been labelled as myeloproliferative variant of HES (HES-MPD
or MP-HES) (Klion et al, 2003, 2004b) or as eosinophilia
associated-systemic mast cell disease (SM-CEL) (Pardanani
et al, 2003a, 2004), a distinction that is therapeutically
irrelevant, given that presence of the fusion predicts Gleevec�responsiveness. Fourteen of the 15 FIP1L1-PDGFRA+ patients
(93%), of over 220 patients tested at our institution, have been
found to have SM-CEL/HES-MPD (one patient had CEL by
WHO criteria). This data suggests that the phenotypic
spectrum associated with the FIP1L1-PDGFRA mutation, at
least as detected by our FISH methodology, is quite narrow
and may be largely restricted to SM-CEL/HES-MPD. The latter
point will need to be confirmed through multi-institutional
effort that employs uniform diagnostic criteria, including
measurement of serum tryptase levels and expert examination
of bone marrow sections using stains that highlight the
relatively subtle mast cell infiltrates in such cases (Pardanani
et al, 2004; Pardanani, 2005).
All individuals carrying the FIP1L1-PDGFRA mutation
achieve a complete haematological remission with 100–
400 mg/d of Gleevec�, which is considered first-line treatment
for this cohort (summarised in Table VI). The drug is taken with
a full glass of water, once a day and always with meals to avoid
upper gastrointestinal irritation. Drug side effects include
Table V. Continued.
Chromosome
affected Karyotype Molecular phenotype
Clinicopathological
presentation References
10 Trisomy 10
t(10; 11) (p14; q21)
HES
AML Eo
Gotlib (2005)
Broustet et al (1986)
11 NA NA NA
12 Ins (12; 8) (p11; p11p22) FGFR1OP2-FGFR1 EMS Grand et al (2004b)
13 NA NA NA
14 NA NA NA
15 t (15; 21) (q13; q22)
+ 15
+ 15;) Y
MDS
CEL
CEL
Brito-Babapulle (1997)
Oliver et al (1998)
Weide et al (1997)
16 t(16; 21) (p11; q22)
Inv (16) (p13q22)
t(16,16) (p13; q22)
NA
CBFb-MYH11
AML Eo
AML M4EoAML M4 Eo
Mecucci et al (1985)
Le Beau et al (1983)
Le Beau et al (1983)
17 Isochromosome 17
Add (17) (q25)
HES
HES
Mitelman et al (1975)
Rotoli et al (2004)
18 NA NA NA
19 NA NA NA
20 Del 20 (q11; q12) HES Brigaudeau et al (1996)
21 Trisomy 21 HES Kusanagi et al (1998)
22 NA NA NA
X NA NA NA
Y )YShort Y
Y, del (15q22)
c-N-ras activation HES
CEL
HES
Needleman et al (1990)
Flannery et al (1972)
Goffman et al (1983)
Complex cytogenetics XYY, t (3; 5), +8,+mar
4q+,)5,+mar
der(7);)3,)11,)13,)15)21,+14,+11;del (5)q31+8,+19,+2q,)6q
NA
NA
NA
NA
NA
HES
CMPD
CEL
CEL
CEL with AT
Bitran et al (1977)
Ellman et al (1979)
Wolz et al (1993)
Bigoni et al (2000)
Cools et al (2004)
HES, hypereosinophilic syndrome; CMPD, chronic myeloproliferative disorder; CEL, chronic eosinophilic leukaemia; MDS, myelodysplastic syn-
drome; EMS, eosinophilic mastocytosis; MS, mastocytosis; CML, chronic myeloid leukaemia; AML Eo, acute eosinophilic leukaemia; CMML, chronic
myelomonocytic leukaemia; JMML, juvenile myelomonocytic leukaemia; NA, data not available; AT, acute transformation.
Review
ª 2006 The AuthorsJournal Compilation ª 2006 Blackwell Publishing Ltd, British Journal of Haematology, 133, 468–492 475
Table
VI.
SummaryofFIP1L1-PDGFRAstudies,includingim
atinib-response
data.
Reference
Total
number
ofcases
(male)
Eligibility(number)
Method
(number
tested
forFIP1L1-
PDGFRA)
FIP1L1-
PDGFRA
positive
cases
Total
imatinib
treated
Imatinib
dose
(positive
cases)
Imatinib
response
(positive
cases)
Imatinib
dose
(negative
cases)
Imatinib
response
(negative
cases)
(%)
Other
abnorm
alities
Pardanani
etal
(2005)
830(N
G)
Unselected
patients
witheosinophilia
and/orSM
CD
FISH
(all)
32 (4%)
11/14
(79%
)
100–400mg/d
11/11
(100%)CHR
NA
NA
NA
Roche-Lestienne
etal
(2005)
35(23)
HES/WHO
+norm
al
cytogenetics
RT-PCR
(n¼
35)
FISH
(n¼
29)
6/35
(17%
)
9/35
(26%
)
100–200mg/d
5/5
(100%)CHR
100–200mg/d
1/4
(25%
)CHR
T-cellclonality
11/35(31%
)
LaStarza
etal
(2005)
26(17)
HES/WHO
(n¼
20);
non-secondary
eosinophilia
>1Æ5·10
9/l
(n¼
6)
FISH
(n¼
26)
RT-PCR
(n¼
4)
10/26
(38%
)
15/26
(58%
)
100–400mg/d
7/7
(100%)CHR
200–600mg/d
2/5
(20%
)CHR
PDFRB,FGFR1,
ETV6,
ABL1–
notrearranged
Vandenberghe
etal
(2004)
17(13)
HESorCEL/W
HO
(clonal
T-cell
casesexcluded)
RT-PCR
(n¼
17)
FISH
(n¼
10)
8/17
(47%
)
5/17
(29%
)
100mg/d
4/4
(100%)CHR
100mg/d
0/1
NA
Pardanani
etal
(2004)
89(N
G)
Eosinophilia
>1Æ5·10
9/l
(Ph+and
t(5;
12)(q33;p13)
excluded)
FISH
(n¼
89)
11/89
(12%
)
26/89
(29%
)
100–400mg/d
8/8
(100%)CHR
100–400mg/d
4/18
(22%
)PR
NA
Cools
etal
(2003)
17(13)
HES/WHO
(n¼
16);
AML(n
¼1)
RT-PCR
(n¼
17)
FISH
(n¼
1)
9/16
(56%
)
11/17
(65%
)
100–400mg/d
5/5
(100%)CHR
100–400mg/d
4/5
(80%
)CHR
PDGFRA,
PDGFRB,KIT
–
nomutations
Klionet
al
(2003)
32(16)
HES/WHO
(n¼
15);
helminth
(n¼
6);
SMCD
(n¼
3);
other
(n¼
8)
RT-PCR
(n¼
11)
5/11
(45%
)
6/32
(19%
)
400mg/d
5/5*
(100%)CHR
NA
NA
AllthreeSM
CD
caseswereKIT
D816V
+
Klionet
al
(2004b)
8(8)
MHES
‘myeloproliferative
variant’of
HES(n
¼7);
ALL(n
¼1)
RT-PCR
(n¼
8)
7/8
(88%
)
7/8
(88%
)
400mg/d
7/7
(100%)CHR
NA
NA
NA
Pardananiet
al
(2003a)
5 (NG)
SMCD-H
ES
FISH
(n¼
5)
RT-PCR
(n¼
1)
3/5
(60%
)
5/5
(100%)
100–400mg/d
3/3
(100%)CHR
100–400mg/d
0/2
2/5caseswere
KIT
D816V
+;
nonehad
Ph,
t(5;
12)(q33;p13)
orKIT
orPDGFRB
mutations
Review
ª 2006 The Authors476 Journal Compilation ª 2006 Blackwell Publishing Ltd, British Journal of Haematology, 133, 468–492
Table
VI.
Continued.
Reference
Total
number
ofcases
(male)
Eligibility(number)
Method
(number
tested
forFIP1L1-
PDGFRA)
FIP1L1-
PDGFRA
positive
cases
Total
imatinib
treated
Imatinib
dose
(positive
cases)
Imatinib
response
(positive
cases)
Imatinib
dose
(negative
cases)
Imatinib
response
(negative
cases)
(%)
Other
abnorm
alities
Martinelliet
al
(2004)
55 (NG)
HES/WHO
RT-PCR
(n¼
55)
13/55
(24%
)
31/55
(56%
)
100–400mg/d
13/13
(100%)CHR
100–400mg/d
1/18
(6%)PR
PDGFRB-TEL,
FGFR1-BCRand
BCR-A
BLnotdetected
Schoch
etal
(2004)
40 (27)
Eosinophilia
nos
FISH
(n¼
40)
Chromosome
banding
analysis
(n¼
37)
RT-PCR
(n¼
4)
4/40
(10%
)
NA
NA
NA
NA
NA
Clonal
cytogenetic
abnorm
alitiesnoted
insixpatients
(includingonewith
FIP1L
1-PDGFRA)
*Oneadditional
patient(FIP1L
1-PDGFRAmutationstatusunkn
own)also
had
complete
remissionto
imatinib
therapy.
n,number;HES,idiopathichypereosinophilicsyndrome;WHO,WorldHealthOrganization;CEL,chroniceosinophilicleukaem
ia;Ph,Philadelphiachromosome;AML,acutemyeloid
leukaem
ia;SM
CD,
system
icmastcelldisease;ALL,acutelymphoblasticleukaem
ia;SM
CD-H
ES,eosinophiliaassociated-SMCD;nos,nototherwisespecified;RT-PCR,reversetranscription-polymerasechainreaction;FISH,
fluorescence
insitu
hybridisation;N
G,n
otgiven;N
A,n
otapplicable;C
HR,completehaematologicalresponse;P
R,p
artialresponse;PDGFRA,p
latelet-derived
growth
factorreceptor(PDGFR)-a;
PDFRB,
PDGFR-b;FGFR1,
fibroblast-derived
growth
factorreceptor1.
Review
ª 2006 The AuthorsJournal Compilation ª 2006 Blackwell Publishing Ltd, British Journal of Haematology, 133, 468–492 477
periorbital and peripheral oedema, diarrhoea, nausea, muscle
cramps, fatigue, bone pain and rash. Peripheral blood screening
for FIP1L1-PDGFRA, using either FISH or RT-PCR, can be
performed to monitor molecular response to treatment at 3–
6 month intervals in the first year and at 6–12 months interval
afterwards. The cumulative data indicates that, after initial
induction therapy, most FIP1L1-PDGFRA+ patients [barring a
small minority (Klion et al, 2004b; Vandenberghe et al, 2004)],
achieve molecular remission within weeks to months of starting
Gleevec� therapy, regardless of whether nested RT-PCR (Klion
et al, 2004b; Martinelli et al, 2004; Vandenberghe et al, 2004; La
Starza et al, 2005; Roche-Lestienne et al, 2005) or interphase
FISH (Pardanani et al, 2003a, 2004; La Starza et al, 2005) is used
as the monitoring tool. Given the short follow up of published
reports and the rarity of such cases, it is currently unknown
whether patients who fail to achieve a molecular remission have
a different natural history as compared to those achieving such a
remission. For the former group, is it possible that, similar to
BCR-ABL in CML (Roche-Lestienne et al, 2002, 2003; Deininger
et al, 2005), resistance-inducing mutations in the PDGFRA
kinase domain predate initiation of Gleevec� therapy and may
be present at diagnosis? While a FIP1L1-PDGFRA mutation
(T674I) that is homologous to the resistance-inducing, ‘gate-
keeper’ T315I mutation in BCR-ABL has been described for two
cases of FIP1L1-PDGFRA+CEL in blast crisis (both in the setting
of an aberrant karyotype) (Cools et al, 2003; von Bubnoff et al,
2005), the issue of whether this mutation arises without selective
pressure from Gleevec� has not been studied thus far. Whether
the FIP1L1-PDGFRA T674I mutation remains sensitive to
higher doses of Gleevec�, as do some BCR-ABL mutations
(Corbin et al, 2003), is currently unknown.
PDGFRB-rearranged eosinophilic disorders
Golub et al (1994) first reported fusion of the tyrosine kinase
encoding region of PDGFRB to the ets-like gene, ETV6
(previously known as tel) in a patient with chronic monom-
yelocytic leukaemia (CMML) and the t(5; 12)(q33; p13)
cytogenetic abnormality. Since then, other fusion transcripts
have been cloned, wherein PDGFRB is fused to the N-
terminal segment of a partner protein that encodes for one or
more oligomerisation domains (Table VII) [summarised in
(Pardanani & Tefferi, 2004; Gotlib, 2005)]. These patients
carry 5q31–33 chromosomal rearrangements and generally
present as atypical CML or a hybrid MPD/MDS syndrome
(CMML, juvenile monomyelocytic leukaemia, etc.), fre-
quently with associated eosinophilia. Translocation t(5; 12),
however, is a relatively rare abnormality. A Mayo Clinic
review of 56 709 cases identified only 25 such cases (0Æ04%).
Of the 11 patients for whom clinical data was available, only
three had eosinophilia. Further, in a cohort of 213 CMML
patients, of which 205 had karyotype analysis, none were
found to carry t(5; 12), even though 34% had other
cytogenetic abnormalities (Onida et al, 2002). Importantly,
as shown elegantly in a study by Baxter and colleagues, for
patients carrying translocations involving 5q31–33, the mere
finding of a 5q33 breakpoint (where PDGFRB is assigned) in
patients with a myeloid disorder does not necessarily indicate
that PDGFRB is involved (Baxter et al, 2003). Conversely,
involvement of 5q31 does not exclude PDGFRB involvement
given that translocations may be complex at the molecular
level. Hence, molecular studies are essential in patients with
5q31–33 translocations to confirm or exclude PDGFRB
rearrangement, given the predictive value for Gleevec�responsiveness of such a finding. Other novel translocations
involving PDGFRB for which the partner genes remain to be
identified have been reported (Table VII) (Baxter et al, 2003;
Ketterling et al, 2004). As summarised in Table VII, Glee-
vec� therapy has in most cases resulted in complete
haematological and/or cytogenetic remissions in patients with
PDGFRB gene fusions.
FGFR1-rearranged eosinophilic disorders
The rearrangement, and consequent activation, of fibroblast
growth factor receptor 1 (FGFR1) is associated with a syndrome
known as the 8p11 myeloproliferative syndrome (EMS) or stem
cell leukaemia lymphoma syndrome (SCLL). EMS is an
aggressive myeloproliferative disorder frequently associated
with eosinophilia and T-cell lymphoblastic lymphoma (Mac-
donald et al, 2002). Both myeloid and lymphoid lineage cells
exhibit the 8p11 translocation, thus demonstrating the stem cell
origin of this disease. Clinically, a biphasic course is frequently
observed – a relatively short chronic phase, followed by
transformation into acute leukaemia with a poor overall
prognosis. While intensive chemotherapy with allogeneic stem
cell rescue is considered the only potential curative therapy for
EMS, the use of FGFR1-targeting small molecule kinase
inhibitors such as protein kinase C (PKC) 412 (an N-benzoyl
derivative of the naturally occurring alkaloid staurosporine) for
treating EMS patients is currently being investigated (Chen
et al, 2004b). Similar to PDGFRB, the FGFR1 fusion proteins
are constitutively active tyrosine kinases, wherein the N-
terminal partner protein contributes self-association do-
main(s). Following ZNF198-FGFR1, numerous other chimaeric
genes resulting from FGFR1 rearrangement, all with an exon 9
breakpoint, have been identified to date (summarised in
Table VIII). Of note, Roumiantsev et al (2004) have modelled
EMS and atypical CML (resembling human disease) in mice
using ZNF198-FGFR1 and BCR-FGFR1 fusion constructs,
respectively, in the murine bone marrow transduction/trans-
plantation system. In the EMS model, the FGFR1 Y766F
mutation was found to attenuate both myeloid and lymphoid
diseases, thus implicating phospholipase C that disrupts Grb2
binding was found to cause EMS-like disease. These data
implicate different signalling pathways originating from both
the FGFR1 kinase as well as the fusion partner in the
pathogenesis of atypical CML and EMS. Further, these mouse
models potentially serve as a platform for testing drugs that
target dysregulated FGFR1, such as PKC412.
Review
ª 2006 The Authors478 Journal Compilation ª 2006 Blackwell Publishing Ltd, British Journal of Haematology, 133, 468–492
Table
VII.Su
mmaryofreportsdescribingPDGFRB-fusiongenes,includingim
atinib-response
data.
Reference
Totalnumber
ofcases(m
ale)
Clinical
presentation
Cytogeneticsdata
provided
PDFGRBfusion
partner
Reciprocal
transcript
detected?
Imatinib
dose
Imatinib
response
Other
pertinent
references
Grandet
al(2004a)
1(1)
•aC
ML,eosinophilia
•t(5;
15)(q33;q22)
•p53B
P1
No
300–400mg/d
PHR
Vizmanoset
al(2004a)
1(1)
•aC
ML,eosinophilia
•t(5;
14)(q33;q24)
•NIN
Yes
200–400mg/d
CHR/CCR
Morerioet
al(2004)
1(1)
•JM
ML,eosinophilia
•46,XY,t(5;17)(q33;p11Æ2)
•HCMOGT-1
No
NA
NA
Wilkinsonet
al(2003)
1(0)
•MDS/MPD,eosinophilia
•t(1;
5)(q23;q33)
•PDE4D
IP
(myomegalin)
No
NG
CHR
Golubet
al(1994)
1(?)
•CMML
•t(5;
12)(q33;p13)
•ETV6(TEL)
No
NA
NA
Wlodarskaet
al(1995)
Apperleyet
al(2002)
4(4)
•chronic
MPD,
eosinophilia
•46,XY,t(5;12)(q33;p13)
•ETV6(TEL)
(3of4patients)
NA
400–800mg/d
CHR/CCR
Pitiniet
al(2003b)
Kulkarniet
al(2000)
1(1)
•aC
ML,eosinophilia
•46,XY,t(5;10)(q33;q21Æ2)
•H4/D10S170
No
NA
NA
Schwalleret
al(2001)
Garciaet
al(2003)
1(1)
•aC
ML,eosinophilia
•46,XY,t(5;10)(q33;q22)
•H4/D10S170
NG
400mg/d
CHR/CCR
Ross
etal
(1998)
1(1)
•CMML,eosinophilia
•t(5;
7)(q33;q11Æ2)
•HIP1
No
NA
NA
Magnussonet
al(2001)
1(1)
•CMML
•46,XY,t(5;17)(q33;p13)
•Rabaptin-5
No
NA
NA
Abeet
al(1997)
1(0)
•AML,eosinophilia
•46,XX,t(5;14)(q33;q32),
t(7;
11)(p15;p15)
•CEV14
No
NA
NA
Baxteret
al(2003)
1(1)
•aC
ML,eosinophilia
•t(3;
5)(p21;q31)
•Notidentified
NA
NA
NA
Kim
etal
(2005)
1(?)
•CMML,eosinophilia
•t(5;
12)(q31;p13),
t(1;
7)(q10;p10)
•Notidentified
NA
NA
NA
Ketterlinget
al(2004)
3(N
G)
•NG
•t(1;
5)(q21;q33)
•t(5;
14)(q33;q32)
•t(5;
16)(q33;p13Æ1)
•Notidentified
NA
NA
NA
CML,chronic
myeloid
leukaem
ia;aC
ML,atypical
(Philadelphia
chromosome-negative)
CML;MDS,
myelodysplastic
syndrome;
MPD,myeloproliferative
disorder;CMML,chronic
myelomonocytic
leukaem
ia;JMML,juvenilemyelomonocyticleukaem
ia;A
ML,acutemyeloid
leukaem
ia;N
G,n
otgiven;N
A,n
otapplicable;C
H,completehaematologicalresponse;C
C,completecytogeneticresponse;P
H,
partial
haematologicalresponse;PDGFRB,platelet-derived
growth
factorreceptor-b.
Review
ª 2006 The AuthorsJournal Compilation ª 2006 Blackwell Publishing Ltd, British Journal of Haematology, 133, 468–492 479
Table
VIII.
SummaryofreportsdescribingFGFR1-fusiongenes.
Reference
Totalnumber
ofcases(m
ale)
Clinical
presentation
Cytogeneticsdata
provided
FGFR1
fusionpartner
Reciprocal
transcript
detected?
Other
pertinent
references
Walzet
al(2005)
1(0)
aCML,eosinophilia,
basophilia,monocytosis
47,XX,t(8:17)(p11;q23),+20
MYO18A
No
Belloniet
al(2005)
1(0)
AML-M
4,eosinophilia,
monocytosis
t(7;
8)(q34;p11)
TIF1
Yes
Grandet
al(2004b)
1(1)
T-lym
phoblastic
lymphoma,
eosinophilia
fiAML
ins(12;8)(p11;p11p12)
FGFR1O
P2
No
Guasch
etal
(2003)
1(1)
AML-M
0,eosinophilia
45,X,t(8;19)(p12;q13Æ3),)Y
HERV-K
No
Guasch
etal
(2000)
1(1)
MPD,eosinophilia
fiAML
46,XY,t(8;9)(p12;q33){8}/48,
idem
,+der(9)t(8;9);+21{12}
CEP110
Yes
Dem
irogluet
al(2001),
Fioretoset
al(2001)
•1(1)
•2(0)
•MPD,eosinophilia,
basophilia
fiAML
•aC
ML,eosinophilia,
basophilia
•46,XY,t(8;22)(p11;q11),
?dup(9)(q34;q34)
•t(8;
22)(p11;q11)
BCR
Yes
Piniet
al(2002),
Muratiet
al(2005)
Popovici
etal
(1999)
2(2)
•MPD,eosinophilia
fiPVfi
AML,
•PVfi
AML
46,XY,t(6;8)(q27;p11)
FOP
Yes
Vizmanoset
al(2004b)
Popovici
etal
(1998)
2(N
G)
•T-lmyphoblastic
lymphoma/MPD
eosinophilia
fiAML
•B-A
LL
•48,XX,t(8;13)(p12;q12),
+der(13)t(8;
13)(p12;q12),
+19{4}/51,idem
,+6,+der(8),t(8;
13)
(p12;q12),+der(13),t(8;13)(p12;q12){2}
•t(8;
13)(p12;q12)
FIM
(synonym
ous
withZNF198)
Yes
Smedleyet
al(1998)
2(N
G)
T-lmyphoblastic
lymphoma/MPD,eosinophilia
t(8;
13)(p11;q11-12)
RAMP(synonym
ous
withZNF198)
No
Xiaoet
al(1998)
4(N
G)
?t(8;
13)(p11;q11-12)
ZNF198
?
Reiteret
al(1998)
5(N
G)
MPD/lym
phoma,
eosinophilia
(individual
patient
detailsnotprovided)
t(8;
13)(p11;q12)
ZNF198
No
Matsumoto
etal
(1999)
Sohal
etal
(2001)
•1(1)
•1(1)
•1(0)
•1(1)
•aC
ML,SM
CD
•AML
•T-lym
phoma/MPD,eosinophilia
•T-lym
phoma/MPD,eosinophilia
•46,XY,t(8;17)(p11;q25)
•47,XY,t(8;11)(p11;p15),+8,)17,
+i(17q)
•46,XX,t(8;12)(p11;q15)
•46,XY,ins(12;8)(p11;p11p21)
•FGFR1predictedto
be
disruptedin
allfourcases
•FGFR1partner
genes
notidentified
NA
FGFR1,fibroblast-derived
growth
factorreceptor1;aC
ML,atypical(Philadelphiachromosome-negative)
chronicmyeloid
leukaem
ia;M
PD,m
yeloproliferative
disease;A
ML,acutemyeloid
leukaem
ia;P
V,
polycythaemia
vera;B-A
LL,B-cellacute
lymphoblastic
leukaem
ia;SM
CD,system
icmastcelldisease;NG,notgiven;NA,notapplicable.
Review
ª 2006 The Authors480 Journal Compilation ª 2006 Blackwell Publishing Ltd, British Journal of Haematology, 133, 468–492
Idiopathic eosinophilia
Once secondary eosinophilia is considered unlikely (Tables I–
IV), a working diagnosis of primary eosinophilia is made and a
bone marrow biopsy with appropriate cytogenetic, molecular,
histochemical and immunophenotypic studies is recommen-
ded in order to characterise the process further as either clonal
or idiopathic eosinophilia (see above discussion on clonal
eosinophilia). HES is a subset of idiopathic eosinophilia that
fulfils the traditional criteria of a persistent (>6 months)
increase in AEC (>1Æ5 · 109/l) associated with target organ
damage (Chusid et al, 1975). However, evidence from both
X-linked clonality studies (Chang et al, 1999; Malcovati et al,
2004) and long-term follow up of affected patients suggest that
at least some patients with HES harbour an underlying clonal
myeloid malignancy that could progress into frank acute
leukaemia or MPD (Owen & Scott, 1979; Yoo et al, 1984;
Brown & Stein, 1989; Needleman et al, 1990). On the other
hand, the demonstration of a clonal (Simon et al, 1999) or
phenotypically abnormal (Simon et al, 1999) T-cell population
in other patients with HES suggests the alternative possibility
of a true secondary process with some of these patients
progressing into clinically overt lymphoma (Butterfield, 2001).
Clinical manifestations
As is the case with clonal eosinophilia, over 90% of patients
with HES are males and the disease is rare in children (Chusid
et al, 1975; Yildiran & Ikinciogullari, 2005). Clinical manifes-
tations are markedly heterogeneous and the disease can either
be completely asymptomatic or involve multiple organs
including the skin (pruritus, urticaria, angioedema, erythema-
tous papules or nodules, mucosal ulcers), the heart (fibro-
blastic endocarditis, valvular disease, mural thrombi,
cardiomyopathy, elevated troponin levels), the nervous system
[sensorimotor polyneuropathies, mononeuritis multiplex, iso-
lated central nervous system (CNS) vasculitis, optic neuritis,
acute transverse myelitis], the lung (pulmonary infiltrates, lung
nodules, pleural effusion), the gastrointestinal system (hepa-
tosplenomegaly, gastroenteritis, sclerosing cholangitis), the
haematopoietic system (cytopenias, bone marrow fibrosis)
and the kidney (thrombotic microangiopathy) (Fauci et al,
1982; Leiferman et al, 1982; Harley et al, 1983; Moore et al,
1985; Lefebvre et al, 1989; Weller & Bubley, 1994; Ommen
et al, 2000; Liapis et al, 2005). In essence, therefore, any organ
is vulnerable to eosinophilia-associated tissue damage although
the major tissue targets are the heart, the nervous system, the
skin and the upper and lower respiratory tract including the
lung parenchyma. In addition, thromboembolic disease invol-
ving the cardiac chambers (Kocaturk & Yilmaz, 2005) as well
as both venous (Liao et al, 2005) and arterial (Ponsky et al,
2005) vessels are not infrequent.
Regarding clinical course, it is important to remember that
HES is a potentially fatal disease with a less than 50% reported
10-year survival (Lefebvre et al, 1989), especially in cortico-
steroid-resistant cases with cardiac involvement. However,
future survival figures are expected to be better because
FIP1L1/PDGFRA-positive cases are no longer considered as
HES and their inadvertent inclusion in older studies (pre-
Gleevec� era) probably contributed to the reported poor
survival (Lefebvre et al, 1989). Similarly, certain clinical
presentations, including recurrent or persistent angioedema
and increased serum IgE levels, have been associated with the
female gender and a more indolent clinical course free of
cardiac involvement (Gleich et al, 1984; Chikama et al, 1998).
Laboratory evaluation
In addition to bone marrow biopsy and cytogenetic studies,
evaluation of primary eosinophilia should include serum
tryptase (an increased level suggests SM-CEL and warrants
bone marrow histochemical studies for tryptase, mast cell
immunophenotyping and molecular studies to detect either
FIP1L1/PDGFRA or KITD816V) (Pardanani et al, 2004), T-cell
immunophenotyping as well as T-cell receptor antigen gene
rearrangement analysis (a positive test suggests an underlying
clonal or phenotypically abnormal T-cell disorder and war-
rants measurement of IL-5 as well as consideration of T-cell-
directed therapy) (Butterfield, 2001), serum IL-5 (an elevated
level requires careful evaluation of the bone marrow as well as
the T-cell gene rearrangement studies for the presence of a
clonal T-cell disease and treatment with interferon-a might be
considered because of the drug’s effect on down-regulating IL-
5 production by Th2 cells) (Schandene et al, 1996; Butterfield,
2001; Simon et al, 2001) and serum IgE level (patients with
increased IgE level might respond better to corticosteroids and
be at a lower risk of developing eosinophilia-associated heart
disease) (Bush et al, 1978; Gleich et al, 1984).
Initial evaluation of the patient with primary eosinophilia
should also include laboratory tests to look for eosinophilic-
mediated tissue damage. In apparently asymptomatic patients,
these include echocardiogram, chest X-ray, pulmonary func-
tion tests and measurement of serum troponin levels. Increased
level of serum cardiac troponin has been shown to correlate
with the presence of cardiomyopathy in HES and recent
studies have suggested a predictive role for drug-induced
cardiogenic shock during treatment with Gleevec� (Sato et al,
2000; Pitini et al, 2003a). In symptomatic patients, tissue
biopsy might be required but not always essential to document
causality.
Treatment
There is currently no consensus regarding the management of
asymptomatic patients with HES with no evidence of organ
damage. One can argue instituting specific therapy, even in
such cases, to prevent long-term ill effects from chronic organ
exposure to excess eosinophils. However, there is no systematic
study that supports such a concern and long term drug therapy
has its own potential danger. Therefore, we currently prefer to
Review
ª 2006 The AuthorsJournal Compilation ª 2006 Blackwell Publishing Ltd, British Journal of Haematology, 133, 468–492 481
closely monitor rather than to treat asymptomatic patients,
regardless of the degree of eosinophilia. Accordingly, we
recommend measurement of serum troponin level every 3–
6 months and an echocardiogram every 6–12 months.
For the treatment of symptomatic patients with HES, the
first-line drug of choice is prednisone (starting dose of 1 mg/
kg/d) because of the rapidity and reliability of its effect.
However, despite a near 70% overall response rate (Parrillo
et al, 1978), relapses off therapy are usual and either a
substitute drug or a steroid-sparing agent soon becomes
necessary. In this regard, interferon-a (starting dose 3 million
units three times a week) (Butterfield & Gleich, 1994; Ceretelli
et al, 1998; Yoon et al, 2000; Baratta et al, 2002) and
hydroxyurea (starting dose 500 mg twice a day) (Parrillo et al,
1978) have respectively served these roles by producing
remissions in the majority of treated patients and are currently
considered second-line drugs of choice. In true HES (i.e.
FIP1L1/PDGFRA-negative), low-dose Gleevec� (100 mg/d) is
unlikely to produce durable complete remissions (Pardanani
et al, 2004). A higher dose of the drug (400 mg/d), however,
might induce partial remissions (Pardanani et al, 2004) and in
some instances a complete remission (Cools et al, 2003), thus
making Gleevec� a reasonable third-line drug of choice.
During Gleevec� therapy for patients with HES, it is
important to recognise the possibility of drug-induced acute
cardiac shock (Pardanani et al, 2003b; Pitini et al, 2003a) as
well as treatment-associated oligospermia (Seshadri et al,
2004). The former is managed by the concomitant use of
systemic corticosteroid therapy, which is recommended in the
presence of either elevated serum troponin level or an
abnormal echocardiogram (Pitini et al, 2003a).
In patients that are refractory to usual therapy in HES,
treatment agents that have been used with some efficacy
include chlorambucil (Weller & Bubley, 1994), etoposide (Smit
et al, 1991), cyclosporine (Nadarajah et al, 1997), vincristine
alone(Spry, 1982) or in combination with mercaptopurine
(Marshall & White, 1989), cladribine (2-chlorodeoxyadeno-
sine) alone (Ueno et al, 1997) or in combination with
cytarabine (Ueno et al, 1997; Jabbour et al, 2005) and
combination of cytarabine and 6-thioguanine (Eakin et al,
1982). Most recently, two monoclonal antibodies were eval-
uated; mepolizumab (SB 240563) targets IL-5 and ale-
mtuzumab (Campath�) targets the CD52 antigen that is
expressed by eosinophils but not neutrophils. Both were
effective in controlling blood eosinophilia as well as disease
symptoms. However, while durable remissions were seen with
maintenance therapy with alemtuzumab (30 mg every
3 weeks) (Pitini et al, 2004; Sefcick et al, 2004), response to
single-dose mepolizumab therapy (1 mg/kg) was relatively
short lived and associated with rebound eosinophilia (Koury
et al, 2003; Plotz et al, 2003; Kim et al, 2004; Klion et al,
2004c). Amongst the aforementioned drug options for salvage
therapy, we prefer to use single agent rather than combination
chemotherapy and avoid the use of alkylating agents. Other-
wise, additional treatment experience is needed to enable
choosing one of the remaining agents over the other. Finally in
drug-refractory HES, myeloablative and non-myeloablative
allogenic peripheral blood stem cell transplants have been used
and were found to reverse organ dysfunction (Juvonen et al,
2002; Ueno et al, 2002; Cooper et al, 2005).
Conclusion
The serendipitous observation of Gleevec� activity in a subset
of patients with systemic mastocytosis associated with eosino-
philia (SM-CEL) (Pardanani et al, 2003c), whose clinical
phenotype might be difficult to distinguish from that of HES
(Gleich et al, 2002), has led to the discovery of FIP1L1/
PDGFRA (Cools et al, 2003) as both a disease-causing
mutation as well as marker of Gleevec� sensitivity. Accord-
ingly, FIP1L1/PDGFRA has now joined a group of oncogenic
kinases, both cytoplasmic and receptor tyrosine kinases, that
are associated with MPD, including BCR/ABL, Janus kinase 2
(JAK2)V617F, KITD816V and others (Cross & Reiter, 2002; De
Keersmaecker & Cools, 2005; Tefferi & Gilliland, 2005).
The myeloproliferation-inducing property of mutant tyro-
sine kinases is consistent with the role of their wild-type
counterparts as relay points of signal transmission for
haematopoietic growth factors. Furthermore, like AML, clonal
myeloproliferation in MPD might represent a multistep
process of multiple mutations that are individually responsible
for cell proliferation/impaired apoptosis (e.g. mutations
involving signal molecules), blockage of cell differentiation
(e.g. mutations involving transcription factors) and overt
leukaemic transformation (e.g. mutations involving tumour
suppressor genes) (Frohling et al, 2005; Reilly, 2005). Such a
contention is supported by the inverse correlation between
Gleevec� treatment efficacy and disease duration/stage in
CML (Goldman, 2004) as well as the lack of correlation
between leukaemic transformation in MPD and JAK2V617F
mutational status (Tefferi et al, 2005; Wolanskyj et al, 2005).
Regardless, it is reasonable to expect retardation of disease
progression in mutant kinase-driven MPD by the early
institution of specific kinase inhibitor therapy.
Controversies aside (Cools et al, 2003), true HES remains
molecularly undefined and not durably responsive to treat-
ment with Gleevec� (Pardanani et al, 2004). Currently
recognised Gleevec�-sensitive mutant kinase targets include
BCR/ABL, FIP1L1/PDGFRA, fusion kinases involving
PDGFRB and KIT mutations other than KITD816V (Pardanani
& Tefferi, 2004). Accordingly, Gleevec� is also ineffective in
FIP1L1/PDGFRA-negative SM-CEL (Pardanani et al, 2003a).
Most recently, the aforementioned Gleevec�-resistant
KITD816V has displayed in vitro treatment sensitivity to other
oral kinase inhibitors including dasatinib (BMS-354825)
(Schittenhelm et al, 2004; Shah et al, 2004) and PKC-412
(Gleixner et al, 2005). Dasatinib is an ATP-competitive, dual
SRC/ABL inhibitor that is greater than 300-fold more potent
than Gleevec� against BCR/ABL-transduced cells and has
demonstrated preclinical activity against 18 of 19 Gleevec�-
Review
ª 2006 The Authors482 Journal Compilation ª 2006 Blackwell Publishing Ltd, British Journal of Haematology, 133, 468–492
resistant BCR-ABL mutations. PKC-412 (N-benzoyl-staurosp-
orine) is an indolocarbazole staurosporine analogue, which
competes for binding to the ATP site on PKC family of serine–
threonine kinases. Both dasatinib and PKC-412 are currently
undergoing clinical trials in systemic mastocytosis (H. Kan-
tarjian, personal communication). On the other hand, effective
targeted therapy in ‘HES’ awaits additional insight in the
molecular pathogenesis of the disease, unless serendipity
strikes again.
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