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

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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

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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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(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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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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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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