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Review article
The FIP1L1-PDGFR␣ fusion tyrosine kinase in hypereosinophilic syndrome
and chronic eosinophilic leukemia: implications for diagnosis, classification,
and management
Jason Gotlib, Jan Cools, James M. Malone III, Stanley L. Schrier, D. Gary Gilliland, and Steven E. Coutre´
Idiopathic hypereosinophilic syndrome
(HES) and chronic eosinophilic leukemia
(CEL) comprise a spectrum of indolent to
aggressive diseases characterized by unexplained, persistent hypereosinophilia.
These disorders have eluded a unique
molecular explanation, and therapy has
primarily been oriented toward palliation
of symptoms related to organ involvement. Recent reports indicate that HES
and CEL are imatinib-responsive malignancies, with rapid and complete hematologic remissions observed at lower doses
than used in chronic myelogenous leuke-
mia (CML). These BCR-ABL–negative
cases lack activating mutations or abnormal fusions involving other known target
genes of imatinib, implicating a novel
tyrosine kinase in their pathogenesis. A
bedside-to-benchtop translational research effort led to the identification of a
constitutively activated fusion tyrosine
kinase on chromosome 4q12, derived
from an interstitial deletion, that fuses the
platelet-derived growth factor receptor-␣
gene (PDGFRA) to an uncharacterized
human gene FIP1-like-1 (FIP1L1). However, not all HES and CEL patients re-
spond to imatinib, suggesting disease
heterogeneity. Furthermore, approximately 40% of responding patients lack
the FIP1L1-PDGFRA fusion, suggesting
genetic heterogeneity. This review examines the current state of knowledge of
HES and CEL and the implications of the
FIP1L1-PDGFRA discovery on their diagnosis, classification, and management.
(Blood. 2004;103:2879-2891)
© 2004 by The American Society of Hematology
Introduction
Protean biologic and clinical presentations characterize idiopathic
hypereosinophilia (HES). HES is similar to other diseases given the
moniker “diagnosis of exclusion,” in that limited understanding of
the pathogenesis of the disease has hampered therapeutic advances.
The demonstration of increased myeloblasts or clonality or the
development of either granulocytic sarcoma or acute myeloid
leukemia helps clarify the origin of some cases of chronic
eosinophilic leukemia.1 In a subset of patients, hypereosinophilia is
related to excessive secretion of eosinophilopoietic cytokines from
a clonal population of lymphocytes.2 The identification of FIP1-like1–platelet-derived growth factor receptor-␣ (FIP1L1-PDGFRA) in
cases of HES/CEL adds to a growing list of activated fusion
tyrosine kinases linked to the pathogenesis of chronic myeloproliferative disorders.3 It is unique, however, because it is the first
description of a gain-of-function fusion protein resulting from a
cryptic interstitial deletion between genes rather than a reciprocal
chromosomal translocation. The FIP1L1-PDGFR␣ fusion protein
transforms hematopoietic cells, and its kinase activity is inhibited
by imatinib at a cellular 50% inhibitory concentration (IC50)
100-fold lower than BCR-ABL.3 Acquisition of an imatinib
resistance mutation in the adenosine triphosphate (ATP)–binding
domain of PDGFRA in a relapsed patient previously responsive to
imatinib supports a critical role for FIP1L1-PDGFR␣ in the
pathogenesis of disease and demonstrates that FIP1L1-PDGFR␣ is
the therapeutic target of imatinib.3 The identification of this novel
From the Division of Hematology, Department of Internal Medicine, Stanford
University School of Medicine, Stanford, CA; Division of Hematology,
Department of Medicine, Brigham and Women’s Hospital, Boston, MA; and
Howard Hughes Medical Institute, Harvard Medical School, Boston, MA.
Submitted June 11, 2003; accepted November 5, 2003. Prepublished online as
Blood First Edition Paper, November 20, 2003; DOI 10.1182/blood-2003-06-1824.
Supported in part by the National Institutes of Health (K23HL04409 [J.G] and
BLOOD, 15 APRIL 2004 䡠 VOLUME 103, NUMBER 8
molecular target in HES and CEL patients will help refine
genotype-phenotype correlations in these diseases and should aid
basic research of the biologic pathways involved in eosinophil
proliferation, differentiation, and signaling.
Epidemiology
HES is predominantly a disease of men (male-female ratio, 9:1)
and is usually diagnosed between the ages of 20 years and 50
years.4 In one series of 50 patients, the mean age at onset was 33
years and the mean duration of disease was 4.8 years (range, 1-24
years) during the time period the patients were followed.4 Rare
cases in infants and children have also been described.5-7
Current classification
In 1968 Hardy and Anderson coined the term “hypereosinophilic
syndrome” to describe patients with prolonged eosinophilia of
unknown cause.8 Chusid et al in 1975 used 3 diagnostic criteria for
HES that are still utilized today: (1) persistent eosinophilia of
1.5 ⫻ 109/L (1500/mm3) for longer than 6 months; (2) lack of
evidence for parasitic, allergic, or other known causes of eosinophilia; and (3) signs and symptoms of organ involvement.9 In the
CA66996 [D.G.G.]) and by the Leukemia and Lymphoma Society (D.G.G.).
J.C. is a “postdoctoraal onderzoeker” of the “F.W.O.-Vlaanderen.”
Reprints: Jason Gotlib, Division of Hematology, Stanford Cancer Center, 875
Blake Willour Dr, Room 2327B, Stanford, CA 94305-5821; e-mail:
[email protected]; or D. Gary Gilliland, Harvard Institutes of Medicine,
4 Blackfan Circle, Rm 418, Boston, MA 02115; e-mail: gilliland@hihg.
med.harvard.edu.
© 2004 by The American Society of Hematology
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GOTLIB et al
recent World Health Organization (WHO) classification, a diagnosis of HES or CEL requires exclusion of reactive causes of
eosinophilia (Table 1), malignancies in which eosinophilia is
reactive (Table 1) or part of the neoplastic clone, and T-cell
disorders associated with abnormalities of immunophenotype and
cytokine production, with or without evidence of lymphocyte
clonality.10 CEL has traditionally been distinguished from HES by
the presence of increased peripheral blood (more than 2%) or
marrow (5%-19%) blasts or the demonstration of a clonal cytogenetic abnormality in the myeloid lineage.10 However, this categoric
distinction is now called into question by the identification of
FIP1L1-PDGFRA in both forms of the disease (see “Implications
of FIP1L1-PDGFRA for the diagnosis, classification, and treatment
of eosinophilic disorders”).
One method for establishing a diagnosis of CEL is demonstration of eosinophil clonality; however, this is frequently not assessed
or is difficult to confirm. Methods for demonstrating clonality
include fluorescence in situ hybridization11 or cytogenetic analysis
of purified eosinophils12 and, also, X chromosome inactivation
analysis in women.13,14 X inactivation–based assessment of clonality is of limited value in HES because most patients are male. To
avoid the emphasis placed on demonstrating clonality of eosinophils, Brito-Babapulle has advocated that, in cases of clonal
eosinophilia, it is sufficient to demonstrate only that eosinophils are
part of a clonal bone marrow disorder and not necessarily part of
the malignant clone, with treatment tailored to the underlying
disease.15 In this scheme, blood eosinophilia is divided into 3
categories: reactive (nonclonal eosinophilia), clonal disorders of
the bone marrow associated with eosinophilia, and HES, which
remains a diagnosis of exclusion.15
Prior reviews have discussed the difficulty in using abnormal
eosinophil morphology (eg, cytoplasmic hypogranularity or vacuolization, abnormal lobation, ring nuclei) to reliably distinguish
reactive from clonal eosinophilia because these cytologic changes
may be present in both conditions.15-17 Roufosse et al have
proposed that disease presentations with CML-like features be
segregated into a “myeloproliferative variant” of HES.18 Clinical
and laboratory features associated with this variant include hepatomegaly, splenomegaly, anemia, thrombocytopenia, bone marrow
dysplasia or fibrosis, and elevated levels of cobalamin. This is in
contrast to a “lymphocytic variant” or T-cell–mediated HES
(discussed in “T-cell–mediated HES”), which typically follows a
more benign course and is usually manifested primarily by skin
disease.18 Some patients exhibit overlapping characteristics of both
variants. Although such groupings may correspond to biologic
subsets of HES, evaluation of a large cohort of patients is required
to validate their prognostic relevance.
Clinicopathologic manifestations
Table 1. Reactive causes of eosinophilia
Allergic/hypersensitivity diseases
Asthma, rhinitis, drug reactions, allergic bronchopulmonary aspergillosis, allergic
gastroenteritis
Infections
Parasitic (strongyloidiasis, Toxocara canis, Trichinella spiralis, visceral larva
migrans, filariasis, schistosomiasis, Ancylostoma duodenale, Fasciola
hepatica, Echinococcus, Toxoplasma, other parasitic diseases)
In one large series, eosinophilia was discovered incidentally in
12% of patients.4 The most common presenting signs and symptoms were weakness and fatigue (26%), cough (24%), dyspnea
(16%), myalgias or angioedema (14%), rash or fever (12%), and
rhinitis (10%).4 Table 2 shows the cumulative frequency of organ
involvement in 105 patients previously compiled from 3
series.4,17,19-21
Bacterial/mycobacterial
Fungal (coccidioidomycosis, cryptococcus)
Viral (HIV, herpes simplex virus [HSV], human T-cell leukemia virus type 2
Hematologic findings
[HTLV-2])
Rickettsial
Connective tissue diseases
Churg-Strauss syndrome, Wegener granulomatosis, rheumatoid arthritis,
polyarteritis nodosa, systemic lupus erythematosus, scleroderma,
eosinophilic fasciitis/myositis
Pulmonary diseases
Bronchiectasis, cystic fibrosis, Loeffler syndrome, eosinophilic granuloma of the
lung
Cardiac diseases
Tropical endocardial fibrosis, eosinophilic endomyocardial fibrosis or myocarditis
Skin diseases
Atopic dermatitis, urticaria, eczema, bullous pemphigoid, dermatitis herpetiformis,
episodic angioedema with eosinophilia (Gleich syndrome)
Gastrointestinal diseases
Eosinophilic gastroenteritis, celiac disease
Although persistent eosinophilia without a clinically identifiable
cause is the sine qua non of HES, the hematologic picture can vary.
Relatively modest elevations in the leukocyte count (eg,
20-30 ⫻ 109/L [20 000-30 000/mm3]) with peripheral eosinophilia
in the range of 30% to 70% are commonly observed,9 but
significantly higher leukocyte counts have also been reported.19,20
Neutrophilia, basophilia, myeloid immaturity, and both mature and
immature eosinophils with varying degrees of dysplasia may be
found in the peripheral blood or bone marrow.19,22 In one series,
anemia was present in 53% of patients, thrombocytopenia was
more common than thrombocytosis (31% versus 16%), and bone
marrow eosinophilia ranged from 7% to 57% (mean, 33%).22
Charcot-Leyden crystals were frequent marrow findings, whereas
increased blasts and myelofibrosis were less often observed.22
Malignancies
Hodgkin and non-Hodgkin lymphoma, acute lymphoblastic leukemia, Langerhans
cell histiocytosis, angiolymphoid hyperplasia with eosinophilia (Kimura
Cardiac disease
disease), angioimmunoblastic lymphadenopathy, solid tumors (eg, renal,
lung, breast, vascular neoplasms, female genital tract cancers)
Immune system diseases/abnormalities
Wiskott-Aldrich syndrome, hyper-IgE (Job) syndrome, hyper-IgM syndrome, IgA
deficiency
Metabolic abnormalities
Adrenal insufficiency
Other
IL-2 therapy, L-tryptophan ingestion, toxic oil syndrome, renal graft rejection
The multistep process of cardiac injury illustrates some of the
pathophysiologic mechanisms contributing to organ damage in
HES (previously reviewed by Fauci et al4 and Weller and Bubley21). In the initial necrotic stage, cardiac disease may be initiated
by eosinophil damage to the endocardium, with local platelet
thrombus subsequently leading to formation of mural thrombi that
have the potential to embolize (thrombotic stage). The contents of
eosinophil granules, including major basic protein and eosinophilic
BLOOD, 15 APRIL 2004 䡠 VOLUME 103, NUMBER 8
FIP1L1-PDGFRA IN HYPEREOSINOPHILIC SYNDROME
cationic protein, may promote endothelial damage and hypercoagulablity, enhancing the thromboembolic risk.23,24 In the later fibrotic
stage, organization of thrombus can lead to fibrous thickening of
the endocardial lining and, ultimately, restrictive cardiomyopathy.4,21 Valvular insufficiency in HES is commonly related to mural
endocardial thrombosis and fibrosis involving leaflets of the mitral
or tricuspid valves.25-27 Table 2 lists manifestations of HES that have
been reported in hematologic, cardiac, and other organ systems.
T-cell–mediated HES
A proportion of HES cases exhibit expansion of abnormal lymphocyte populations. Immunophenotypic features include doublenegative, immature T cells (eg, CD3⫹CD4⫺CD8⫺) or absence of
CD3 (eg, CD3⫺CD4⫹), a normal component of the T-cell receptor
complex.91-93 In patients with T-cell–mediated hypereosinophilia
with elevated immunoglobulin E (IgE) levels, lymphocyte production of interleukin-5 (IL-5)—and in some cases IL-4 and IL-13—
suggests that these T cells have a helper type 2 (Th2) cytokine
profile.18,91,93-95 In a study of 60 patients recruited primarily from
dermatology clinics, 16 had a unique population of circulating T
cells with an abnormal immunophenotype.2 Clonal rearrangement
of T-cell receptor genes was demonstrated in half of these
individuals (8 of 60 total patients). The abnormal T cells secreted
high levels of interleukin-5 in vitro and displayed an activated
immunophenotype (eg, CD25 and/or HLA-DR expression). One
patient during study and 3 at follow-up were diagnosed with T-cell
lymphoma or Se´ zary syndrome, indicating that T cells in some
HES patients have neoplastic potential. The factors that contribute
to malignant transformation in T-cell–associated HES require
further characterization. In some cases, accumulation of cytogenetic changes in T cells and proliferation of lymphocytes with the
CD3⫺CD4⫹ phenotype have been observed.95-97 It is currently
unknown whether subsets of T-cell–associated HES cases also
express the FIP1L1-PDGFRA fusion.
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Cytogenetic and molecular features of
hematologic malignancies with eosinophilia
Several hematologic malignancies are associated with eosinophilia.
Eosinophilia is thought to result from the production of cytokines
(eg, IL-3, IL-5, and granulocyte-macrophage colony-stimulating
factor [GM-CSF]) from malignant cells in T-cell lymphomas,98
Hodgkin disease,99 and acute lymphoblastic leukemias.100,101 In
some cases, isolated eosinophilia may herald the initial diagnosis or
relapse of these conditions.
Over the last 3 decades, the list of chromosomal abnormalities
in cases reported as HES or CEL has grown (reviewed by Bain102).
However, a unique clonal karyotype has not been associated with
these diseases, and most patients exhibit a normal karyotype by
conventional cytogenetics. Although trisomy 8 is frequently detected in these eosinophilic disorders,103-106 it is also observed in
other hematologic malignancies. Three HES case reports have
described balanced reciprocal translocations within or near the
chromosome 4q12 locus of the PDGFRA and KIT tyrosine kinases:
t(3;4)(p13;q12),107 t(4;7)(q11;q32),108 and t(4;7)(q11;p13).109 The
genes involved in these translocations were not identified. In a
recent report, a 6-year-old girl with hypereosinophilia presented
with a t(5;9)(q11;q34) constitutional translocation, involving genes
for the ABL tyrosine kinase and possibly granzyme A on chromosome 5.7 In this case, no mention was made of the use of imatinib.
Eosinophils have been found to be part of the malignant clone in
systemic mastocytosis,110 CML and other chronic myeloproliferative disorders (MPDs), and in specific subtypes of acute myeloid
leukemia (AML). The best-characterized examples in the FrenchAmerican-British classification of AML are M4Eo inv(16)(p13q22)
or t(16;16)(p13;q22),111 resulting in chimeric fusion of the CBF␤
and MYH11 genes, and M2 t(8;21)(q22;q22),112 which links the
AML-1 and ETO genes. Other abnormal karyotypes reported in
AML with eosinophilia include monosomy 7,113 trisomy 1,114
t(10;11)(p14;q21),115 t(5;16)(q33;q22),116 and t(16;21)(p11;q22).117
Table 2. Organ involvement in hypereosinophilic syndrome
Organ system
Hematologic
Cumulative frequency
from 3 studies, % *
100
Examples of organ-specific manifestations
Leukocytosis with eosinophilia; neutrophilia, basophilia, myeloid immaturity, immature and/or dysplastic
eosinophils; anemia, thrombocytopenia or thrombocytosis, increased marrow blasts, myelofibrosis19,21
Cardiovascular
58
Cardiomyopathy,28,29 constrictive pericarditis,30,31 endomyocarditis,32,33 mural thrombi,27,34 valvular
Dermatologic
56
Angioedema,40 urticaria,40 papules/nodules,40 plaques,41 aquagenic pruritis,42 erythroderma,43 mucosal
Neurologic
54
Thromboembolism,50 peripheral neuropathy,50,51 encephalopathy,50,52 dementia,53,54 epilepsy,55 cerebellar
Pulmonary
49
Pulmonary infiltrates,9,58 effusions,9,59 fibrosis,4 emboli,60 nodules/focal ground glass attenuation,61 acute
Splenic
43
Hypersplenism, infarct63
Liver/gallbladder
30
Hepatomegaly,64 focal or diffuse hepatic lesions on imaging,64 chronic active hepatitis,65 hepatic necrosis,66
Ocular
23
Microthrombi,71-73 choroidal infarcts,72 retinal arteritis,73 episcleritis,74 keratoconjunctivitis sicca,74 Adie
Gastrointestinal
23
Ascites,76 diarrhea,77 gastritis,78 colitis,69,78 pancreatitis77
Musculoskeletal
N/A
Arthritis,79,80 effusions,80 bursitis,81 synovitis,82 Raynaud phenomena,83 digital necrosis,84
Renal
N/A
Acute renal failure with Charcot-Leyden crystalluria,87 nephrotic syndrome,88 immunotactoid
dysfunction,27,35,36 endomyocardial fibrosis,37,38 myocardial infarction39
ulcers,44 vesicobullous lesions,45 microthrombi,46,47 vasculitis,48 Wells syndrome49
disease,56 eosinophilic meningitis57
respiratory distress syndrome (ARDS)62
Budd-Chiari syndrome,67 sclerosing cholangitis,68 cholecystitis,69 cholestasis70
syndrome (pupillotonia)75
polymyositis/myopathy85,86
glomerulopathy,89 crescentic glomerulonephritis90
Modified from Weller and Bubley21 and from Brito-Babapulle17 with permission from Elsevier.
N/A indicates not available.
*Data are taken from Fauci et al,4 Spry et al,19 and Lefebure et al.20
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GOTLIB et al
The latter 2 may represent chromosome 16 variants with an
underlying cryptic fusion gene. Eosinophil clonality has been
demonstrated in cases of eosinophilic myelodysplastic syndrome
(MDS) with t(1;7) or dic(1;7) karyotypes.11,118 Eosinophilia is also
a feature of acute and chronic hematologic malignancies with
rearrangements involving transcription factor ETV6 (ETS translocation variant 6, TEL) on chromosome 12p13. Examples include
the ETV6-ABL fusion in t(9;12)(q34;p13) AML119 and, also, the
small subset of chronic myelomonocytic leukemia patients with
t(5;12)(q33;p13), which fuses platelet-derived growth factor receptor-beta (PDGFR␤) on chromosome 5q33 to ETV6.120 In this latter
disease, imatinib produces clinical remissions by inhibiting the
deregulated activity of the fusion tyrosine kinase.121 Proliferation
of eosinophils in some AML, MPD, and MDS cases is associated
with rearrangements involving the long arm of chromosome 5 (eg,
5q31-33) where several genes encoding eosinophilic cytokines
reside.122-124 In a study of 9 patients with MPD or mixed MDS/
MPD and a translocation involving 5q31-33, fluorescence in situ
hybridization (FISH) unmasked disruption of the PDGFRB gene in
6 cases.125 The translocations included t(1;5)(q21;q33), t(1;5)(q22;
q31), t(1;3;5)(p36;p21;q33), t(2;12;5)(q37;q22;q33), t(3;5)(p21;
q31), and t(5;14)(q33;q24). Eosinophilia was noted in 3 of these
patients and noted in an additional case at the time of transformation to AML.125 Recent cloning of the t(1;5)(q23;q33) breakpoint
revealed that PDGFRB is fused to the novel partner protein
myomegalin.126 In a subset of B-cell acute lymphoblastic leukemias, translocation of the IL-3 gene on chromosome 5q31 to the
immunoglobulin heavy chain gene on chromosome 14q32 is
typically associated with eosinophilia.127 In the “stem cell” myeloproliferative disorders, mutation in a pluripotent hematopoietic
progenitor results in a spectrum of diseases including T- or B-cell
lymphoblastic lymphoma, bone marrow myeloid hyperplasia, and
eosinophilia. These poor-prognosis disorders are related to recurrent breakpoints on chromosome 8p11 that involve translocation of
the fibroblast growth factor receptor 1 (FGFR1) gene to 5 currently
identified partner loci: FOP at 6q27,128 CEP110 at 9q33,129
FIM/ZNF198 at 13q12,130 BCR at 22q11,131 and the human
endogenous retrovirus gene (HERV-K) at 19q13.132 Before attributing eosinophilia to HES or CEL, these various hematologic
malignancies should be given diagnostic consideration.
Prognosis
A prior review of 57 HES cases included reports published between
1919 and 1973.9 The median survival was 9 months, and the 3-year
survival was only 12%.9 These patients generally had advanced
disease, with congestive heart failure accounting for 65% of the
identified causes of death at autopsy. In addition to the development of cardiac disease, peripheral blood blasts or a white blood
cell (WBC) count more than 100 ⫻109/L (100 000/mm3) were
associated with a poor prognosis.9 A later report of 40 HES patients
observed a 5-year survival rate of 80%, decreasing to 42% at 15
years.20 In this cohort, poor prognostic factors included the
presence of a concurrent myeloproliferative syndrome, lack of
response of the hypereosinophilia to corticosteroids, existence of
cardiac disease, male sex, and the height of eosinophilia.20 Modern
diagnostic methods and better treatment for cardiovascular disease
probably contribute to improved survival.
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Current treatment
In patients with persistent eosinophilia and organ damage due to
reactive causes or clonal bone marrow disease, therapy should be
directed to the underlying disorder. Some treatment algorithms
have incorporated serial monitoring of eosinophil counts, evaluation of clonality (eg, T-cell–receptor gene rearrangement, immunophenotyping), bone marrow aspiration and biopsy with cytogenetics, and directed organ assessment (eg, echocardiography) to
identify occult organ disease and alternative causes of eosinophilia
that may slowly emerge after an initial diagnosis of HES.15,21 In
patients with HES, corticosteroids (1 mg/kg/d) are indicated for
organ disease and are useful for eliciting rapid reductions in the
eosinophil count.4,21,133 Lack of steroid responsiveness warrants
consideration of cytotoxic therapy. Hydroxyurea is an effective
first-line chemotherapeutic for HES4,21,133; some benefit has also
been reported for second-line agents including vincristine,134-136
pulsed chlorambucil,21 cyclophosphamide,137 and etoposide.138,139
Interferon-␣ (IFN-␣) can elicit long-term hematologic and cytogenetic responses in HES and CEL patients resistant to other
therapies, including prednisone and hydroxyurea.109,140-145 Some
have advocated its use as initial therapy for these diseases.144
Remissions have been associated with improvement in clinical
symptoms and organ disease, including hepatosplenomegaly,140,144
cardiac and thromboembolic complications,109,141 mucosal ulcers,143 and skin involvement.145 IFN-␣ exerts pleiotropic effects
including inhibition of eosinophil proliferation and differentiation.146 Inhibition of IL-5 synthesis from CD4⫹ helper T cells may
be relevant to its mode of action in T-cell–mediated forms of
HES.147 IFN-␣ may also act more directly via IFN-␣ receptors on
eosinophils, suppressing release of mediators including cationic
protein, neurotoxin, and interleukin-5.148 Responses to cyclosporin
A149,150 and 2-chlorodeoxyadenosine have also been reported
in HES.151
Bone marrow/peripheral blood stem cell allogeneic transplantation has been attempted in patients with aggressive disease.
Disease-free survival ranging from 8 months to 5 years has been
reported152-156 with one patient relapsing at 40 months.157 Allogeneic transplantation using nonmyeloablative conditioning regimens
has been reported in 3 patients, with remission duration of 3 to 12
months at the time of last reported follow-up.158,159 Despite success
in selected cases, the role of transplantation in HES is not well
established. Transplantation-related complications including acute
and chronic graft versus host disease as well as serious infections
have been frequently observed.160,161
Advances in cardiac surgery have extended the life of patients
with late-stage heart disease manifested by endomyocardial fibrosis, mural thrombosis, and valvular insufficiency.4,21 Mitral and/or
tricuspid valve repair or replacement26,35-37,162 and endomyocardectomy for late-stage fibrotic heart disease37,163 can improve cardiac
function. Bioprosthetic devices are preferred over their mechanical
counterparts because of the reduced frequency of valve thrombosis.
Leukapheresis can elicit transient reductions in high eosinophil
counts but is not an effective maintenance therapy.164-166 Similar to
other myeloproliferative disorders, splenectomy has been performed for hypersplenism-related abdominal pain and splenic
infarction but is not considered a mainstay of treatment.19,167
Anticoagulants and antiplatelet agents have shown variable success
in preventing recurrent thromboembolism.19,47,50,168
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FIP1L1-PDGFRA IN HYPEREOSINOPHILIC SYNDROME
Imatinib in HES
Table 3 summarizes published case reports and series of patients
with hematologic malignancies associated with eosinophilia who
were treated with imatinib. The first case of imatinib treatment in
HES was reported in 2001.169 The patient was resistant or intolerant
to prior therapies including corticosteroids, hydroxyurea, and
IFN-␣. He was treated with imatinib based on the drug’s efficacy in
CML, with the hypothesis that the 2 diseases may share a common
pathogenetic mechanism. The patient achieved a rapid and complete hematologic remission after taking 100 mg imatinib daily for
4 days. Complete disappearance of peripheral eosinophils occurred
by day 35. Imatinib was decreased to 75 mg daily for headaches,
which still effectively controlled eosinophil levels.
A subsequent report included 5 HES patients treated with 100
mg imatinib daily.170 Four male patients with normal serum levels
of interleukin-5 achieved complete hematologic remissions. One
female patient with high levels of serum interleukin-5 did not
respond to imatinib. All patients who responded were able to
discontinue other treatments.
A third report described a 54-year-old man with HES and organ
involvement including splenomegaly, skin, cardiac, and central
nervous system disease.167 He was resistant to steroids and
chemotherapy, including 2-chlorodeoxyadenosine and cytosine
arabinoside. Before treatment, the WBC count was 9.7 ⫻ 109/L
(9700/mm3) with 68% eosinophils. After 18 days of imatinib (100
mg daily), the patient achieved a complete hematologic remission
with a WBC count of 3.9 ⫻ 109/L (3900/mm3) and 0% eosinophils.
His hematologic response was accompanied by marked symptomatic improvement.
Another study reported the efficacy of 100 to 400 mg imatinib
daily in 5 HES patients and 2 patients with a diagnosis reported as
eosinophilia-associated chronic myeloproliferative disorder (eosCMD).171 At a median follow-up of 17 weeks, 1 eos-CMD and 2
HES patients achieved complete clinical remissions, and an
additional HES patient achieved a partial remission. Screening for
known targets of imatinib, including BCR-ABL, or mutations in the
coding exons of KIT and PDGFRB was negative. In contrast to the
earlier report where complete remitters had normal serum interleu-
2883
kin-5 levels, the current group of responders had high serum levels.
These disparate findings demonstrate that levels of this eosinophilstimulating cytokine are not necessarily predictive of imatinib
responsiveness in HES patients. Although imatinib was generally
well tolerated, one responding HES patient experienced cardiogenic shock within the first week of treatment with a marked
decrease in the left ventricular (LV) ejection fraction. Endomyocardial biopsy revealed eosinophilic myocarditis with evidence of
eosinophil infiltration, degranulation, and myocyte damage. The
patient was successfully treated with high-dose corticosteroids. LV
function recovered, and the patient was restarted on imatinib and
achieved a hematologic remission. More data are needed to
evaluate the role of prophylactic steroids in HES patients with
cardiac disease who receive imatinib treatment.
An additional cohort of 9 symptomatic HES patients (6 male;
median age, 50) was treated with imatinib starting at 100 mg
daily.172 They had received an average of 3 prior therapies. With
median follow-up of 13 weeks, 4 male patients achieved a
complete remission. Three exhibited response within the first 2
weeks of therapy, while the fourth required a dose increase to 400
mg daily at day 28 to attain a normal eosinophil count. Overall,
treatment was well tolerated, with primarily grade 1 toxicities
previously associated with imatinib reported.
The largest study described 16 patients, including 11 treated
with imatinib.3 At presentation, the median eosinophil count was
14.5 ⫻ 109/L (14500/mm3) (range, 4.96 ⫻ 109/L to 53 ⫻ 109/L
[4960/mm3 to 53000/mm3]). Nine of the treated patients had
normal karyotypes. One CEL patient had a clonal cytogenetic
abnormality t(1;4)(q44;q12), and one patient with AML arising
from CEL had a complex karyotype, including trisomies 8 and 19,
add2q, and del6q. Hematologic responses were observed in 10 of
11 HES patients treated with imatinib at doses of 100 to 400 mg
daily. The median time to response was 4 weeks (range, 1 to 12
weeks). Nine of the 10 patients demonstrated sustained hematologic responses (lasting at least 3 months), with a median duration
of 7 months at the time of publication (range, 3 to 15 months). One
patient had a transient response lasting several weeks and failed to
derive benefit from an increase in the imatinib dose. Figure 1 shows
a bone marrow biopsy from the CEL/AML patient with the
Table 3. Published reports of imatinib in HES, CEL, and SM with eosinophilia
Author, year
(reference no.)
Schaller and Burkland,
No. of patients treated
with imatinib
Disease
Responses*
Comments
1
HES
CR
5
HES
4 CR
Ault et al, 2002 (167)†
1
HES
CR
Pardanani et al, 2003
7
HES,
3 CR, 1 PR
9
HES
4 CR
3 responses at imatinib 100 mg mg/d; 1 response at
11
HES/CEL
9 CR
FIP1L1-PDGFRA fusion present in 5 of 9 responders
Klion et al, 2003 (175)
7
HES-MPD
7 CR
Molecular remission in 5 of 6 patients tested for
Pardanani et al, 2003
6
SM with
3 CR
Responders had FIP1L1-PDGFRA fusion and no
2001 (169)†
Gleich et al, 2002
Initial report; rapid hematologic remission on imatinib
100 mg/d
IL-5 levels normal in responders
(170)†
Resolution of 70% eosinophilia in 18 d on imatinib 100
mg/d
(171)†
Cortes et al, 2003
Eos-CMD
(172)†
Cools et al, 2003 (3)
IL-5 levels elevated in responders
400 mg/d
FIP1L1-PDGFRA after 1-12 mo of imatinib
(176)
eosinophilia
D816V KIT mutation
CR indicates complete hematologic remission; PR, partial hematologic remission; Eos-CMD, eosinophilia-associated chronic myeloproliferative disorder; HES-MPD,
myeloproliferative variant of HES; and SM, systemic mastocytosis.
*Refer to individual studies for response criteria.
†FIP1L1-PDGFRA fusion not assessed.
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GOTLIB et al
BLOOD, 15 APRIL 2004 䡠 VOLUME 103, NUMBER 8
Figure 1. Bone marrow biopsy from a patient with
AML and myelofibrosis arising from chronic eosinophilic leukemia. Bone marrow biopsies are shown before (A-B) and after (C-D) imatinib treatment. (A) Marrow
biopsy section (Ai; hematoxylin and eosin; original magnification, ⫻ 4) is hypercellular with scattered eosinophils
(Aii; original magnification, ⫻ 20) and columnar arrays of
immature myeloid cells (Aiii; original magnification, ⫻ 20).
(B) Reticulin stain highlights severe fibrosis (magnified
view, Bii; original magnification, ⫻ 10). After 3 months of
imatinib therapy, (C) marrow biopsy reveals marked
hypocellularity without increased immature myeloid cells
or eosinophils, and (D) reticulin stain shows markedly
diminished fibrosis (original magnification, ⫻ 4 for panels
C and D). After an additional 3 months, the patient
relapsed with bone marrow findings similar to those in
panels A and B. Screening of the FIP1L1-PDGFRA fusion
at the time of relapse revealed the interval development
of an imatinib resistance mutation (T674I) within the
PDGFRA gene.
complex karyotype before imatinib treatment and at the time of
hematologic remission following 3 months of therapy.
The molecular basis for response in most patients was inhibition
of a novel fusion tyrosine kinase, FIP1L1-PDGFR␣, in which a
newly described human gene, FIP1-like-1 (FIP1L1), is fused to
the gene encoding platelet-derived growth factor receptor-␣
(PDGFRA).3 The FIP1L1 gene encodes a protein that is homologous to a previously characterized Saccharomyces cerevisiae
protein, Fip1, a synthetic lethal component of the mRNA polyadenylation apparatus.173 The fusion gene is generated by an interstitial
deletion on chromosome 4q12 rather than a reciprocal translocation.3 FIP1L1-PDGFRA was present in 9 (56%) of 16 HES
patients. In patients for whom FIP1L1-PDGFRA testing was
performed, the fusion was detected with a similar frequency in
treated (5 of 10) and untreated (4 of 6) patients.3 All 5 patients with
the FIP1L1-PDGFRA fusion responded to imatinib.3 However, an
additional 4 patients with durable responses to imatinib lacked
FIP1L1-PDGFRA, indicating that an as yet unidentified target of
imatinib is responsible for HES in these cases.3 To date, no primary
treatment failures to imatinib have been reported in patients with
the FIP1L1-PDGFRA fusion.
The FIP1L1-PDGFRA genotype may cosegregate with a clinical phenotype including myeloproliferative-like HES (HES-MPD),
tissue fibrosis, and increased serum tryptase levels.174,175 The
FIP1L1-PDGFRA fusion was identified in all 7 HES-MPD patients
with elevated serum tryptase levels (all were treated with imatinib
and responded)175; in an earlier companion study, the fusion was
not detected in 4 HES patients with normal serum tryptase or 2
patients with familial eosinophilia. FIP1L1-PDGFRA may also be
related to the pathogenesis of eosinophilic subsets of systemic
mastocytosis (SM). Deletion of the CHIC2 locus, a surrogate for
the FIP1L1-PDGFRA fusion, was detected in imatinib-responsive
patients diagnosed with systemic mastocytosis (SM) and eosinophilia but not in 2 other patients with SM and the KIT Asp816Val
(D816V) mutation who exhibited no response to imatinib.176
Currently, limited data are available regarding imatinib’s ability
to reverse eosinophil-related organ damage. Among 3 HES-MPD
patients with endomyocardial fibrosis and congestive heart failure,
there was no improvement in cardiac disease despite complete
hematologic responses to imatinib.175 However, significant improvement of respiratory symptoms associated with clearing of interstitial infiltrates on chest computed tomography (CT)171,175 and normaliza-
tion of pulmonary function testing have been reported.175 We and others
have demonstrated reversal of myelofibrosis (Figure 1).175
Molecular biology of FIP1L1-PDGFRA
The FIP1L1-PDGFRA fusion gene is created by the del(4)(q12q12),
an 800-kb deletion on chromosome 4q12 (Figure 2).3 The deletion
is not visible using standard cytogenetic banding techniques and
explains why most HES patients with the fusion have an apparently
normal karyotype. One imatinib-responsive HES patient with a
t(1;4)(q44;q12) ultimately led to the identification of the fusion
gene, but in retrospect the translocation was merely a “stalking
horse” for the del(4)(q12q12) that gives rise to the fusion gene.3
The deletion disrupts the FIP1L1 and PDGFRA genes and fuses the
5⬘ part of FIP1L1 to the 3⬘ part of PDGFRA.3 In each patient the
breakpoints in FIP1L1 and PDGFRA are different, but the FIP1L1PDGFRA fusions are always in frame.3 The breakpoints in FIP1L1
are scattered over a region of 40 kb (introns 7-10), whereas the
breakpoints in PDGFRA are restricted to a very small region that
invariably involves PDGFRA exon 12.3 As the 5⬘ part of exon 12 of
PDGFRA is deleted, splicing of FIP1L1 exons to the truncated
exon 12 of PDGFRA occurs by use of cryptic splice sites within
exon 12 of PDGFRA or in introns of FIP1L1 (Figure 3).3,175
FIP1L1-PDGFR␣ has also been discovered in the cell line
EOL-1, derived from a patient with acute eosinophilic leukemia
following hypereosinophilic syndrome. Imatinib and 2 other inhibitors of PDGFR␣, vatalanib and THRX-165724, reduced the
viability of EOL-1 cells and a prominent 110-kDa phosphoprotein,
ultimately identified as FIP1L1-PDGFR␣.177
FIP1L1 is a 520–amino acid protein that contains a region of
homology to Fip1, a yeast protein with synthetic lethal function
that is involved in polyadenylation.174,178 Similar proteins are found
in plants, worm, fly, rat, and mouse. All share the well-conserved
42–amino acid “Fip1” motif (pfam domain no. PF05182; http://
pfam.wustl.edu/cgi-bin/getdesc?acc⫽PF05182), which is also
present in the FIP1L1-PDGFR␣ fusion protein. The exact function
of the human or mouse FIP1L1 protein is not known. Based on the
abundance of FIP1L1 expressed sequence tags (ESTs) in the databases
that are derived from different tissues and cell types, FIP1L1 is predicted
to be under the control of a ubiquitous promoter.
BLOOD, 15 APRIL 2004 䡠 VOLUME 103, NUMBER 8
Figure 2. Fusion of FIP1L1 to PDGFRA. (A) Schematic representation of the
FIP1L1, PDGFR␣, and FIP1L1-PDGFR␣ fusion proteins. NLS indicates nuclear
localization signal; TM, transmembrane region; and JM, juxtamembrane region. (B)
Schematic representation of the 4q12 chromosomal region around the FIP1L1 and
PDGFRA genes. The 800-kb deletion, resulting in the fusion of the 5⬘ part of FIP1L1
to the 3⬘ part of PDGFRA, and the location of 3 bacterial artificial chromosome (BAC)
probes (RPCI11-120K16, RPCI11-3H20, and RPCI11-24O10) are indicated. cen
indicates centromeric side; and tel, telomeric side. (C) Detection of the del(4)(q12q12)
in an HES case by interphase FISH using the BAC probes shown in panel B. Absence
of probe 3H20 and presence of the 2 flanking probes is indicative of the presence of
this specific deletion on one of the chromosomes 4.
Similar to other fusion tyrosine kinases, FIP1L1-PDGFR␣ is a
constitutively active tyrosine kinase that transforms hematopoietic
cells in vitro and in vivo.3,179 FIP1L1-PDGFR␣ phosphorylates
itself and signal transducer and activator of transcription-5 (STAT5)
but, in contrast with the native PDGFR␣, does not activate the
mitogen-activated protein kinase (MAPK) pathway.3,180,181 The
difference in MAPK signaling might be explained by the difference
in subcellular localization, because PDGFR␣ is a transmembrane
protein with ready access to farnesylated RAS, whereas FIP1L1PDGFR␣ is predicted to be cytosolic. In support of this hypothesis,
membrane attachment of PDGFR␤ is critical for its ability to
activate the MAPK pathway.182
The mechanism of constitutive activation of FIP1L1-PDGFR␣
tyrosine kinase activity is not well understood. It would be predicted,
based on analysis of structure-function in all known fusion tyrosine
kinases, including BCR-ABL,183 TEL-PDGFR␤,184 TEL-ABL,185
H4-PDGFR␤,186 HIP1-PDGFR␤,187 and TEL-JAK2,188 that FIP1L1
would contribute a homodimerization motif that serves to constitutively activate the PDGFR␣ kinase. However, we have not
identified a dimerization motif within FIP1L1 that delineates it
from all other known tyrosine kinase fusion partners in cancer.
FIP1L1-PDGFRA IN HYPEREOSINOPHILIC SYNDROME
2885
The genetic analysis of multiple patients may provide a clue to
the mechanism of activation. Most chromosomal translocations
that result in fusion tyrosine kinases occur at highly variable
locations within large introns. Although the genomic breakpoint is
in essence unique for each patient, RNA splicing usually results in
expression of identical fusion proteins. Consistent with this experience, the FIP1L1 genomic breakpoints are variable and may occur
in several introns within the gene. However, the genomic breakpoints
in PDGFRA are quite unusual, in that they all occur within exon 12.
How might conserved breakpoints within exon 12 contribute to
constitutive activation of the PDGFR␣ kinase? Exon 12 of
PDGFRA encodes a portion of the juxtamembrane domain that is
known to serve an autoinhibitory function in the context of other
receptor tyrosine kinases. Disruptions of this domain by missense
mutations, in-frame insertions, or in-frame deletions result in
constitutive activation of the respective tyrosine kinase. For
example, juxtamembrane internal tandem duplications in FLT3
result in its constitutive activation in approximately 25% of cases
of AML.189 Mutation of the juxtamembrane domain of KIT results
in its constitutive activation in most cases of gastrointestinal
stromal cell tumors.190 The juxtamembrane region of PDGFR␤
contains a WW domain with an inhibitory function for kinase
activity, and in-frame point mutations of the WW domain result in
constitutive activation of the kinase.191 Furthermore, mutations in
the WW domain of PDGFR␣ were identified in rare cases of gastrointestinal stromal cell tumors.192 To date, all cloned FIP1L1-PDGFRA fusion
genes result in a truncation of PDGFR␣ within the WW domain,
suggesting that interruption of the WW domain contributes to the
activation of FIP1L1-PDGFR␣. Thus, a plausible hypothesis is that
disruption of PDGFRA exon 12 within the WW domain, in combination
with unregulated expression from the FIP1L1 promoter, are the pivotal
events required for transformation of cells.
There are several important implications from the hypothesis
that the interstitial deletion serves primarily to disrupt the autoinhibitory domain and fuses the kinase to a constitutively activated
Figure 3. Fusion of FIP1L1 to PDGFRA involves the use of cryptic splice sites.
(A) Splicing of exon 11 to exon 12 as it occurs in wild-type PDGFRA. (B) Splicing of
FIP1L1 exons to the truncated exon 12 of PDGFRA as observed in 2 different HES
patients. As the normal splice site in front of exon 12 is deleted, cryptic splice sites in
the introns of FIP1L1 (as in case a) or within exon 12 (as in case b) are used to
generate in-frame FIP1L1-PDGFRA fusions. As a result, the fusion protein sometimes contains a few extra amino acids derived from an intronic sequence of FIP1L1
(as in case a). Sequences from FIP1L1 are shown in lowercase letters and in gray;
PDGFRA sequences are shown in capital letters and in black. Introns are depicted as
lines; exons are shown as blocks. Splice sites are underlined in the sequence. The
spliced RNA sequence and corresponding protein sequence are shown under the
DNA. Cryptic splice sites are indicated with an arrow. Arrowheads indicate where the
breakpoints are located in exon 12 of PDGFRA in cases a and b.
2886
GOTLIB et al
and unregulated promoter. First, it indicates that potential kinase
gene partners need not have dimerization motifs but only an active
promoter to contribute to pathogenesis of disease. Thus, deletions
of varying sizes that each disrupt exon 12 of PDGFRA could
involve a spectrum of genomically diverse genes 5⬘ of the kinase.
This mechanism could even be invoked for very large and highly
variable deletions. In imatinib-responsive HES without a detectable FIP1L1-PDGFRA fusion, it will be important to analyze other
potential partners for PDGFR␣ as well as similar mechanisms of
activation of the other known imatinib-responsive tyrosine kinases.
Another important implication of these findings is that small
interstitial chromosomal deletions that activate tyrosine kinases
may also occur in other hematologic malignancies or solid tumors.
Indeed, it is possible that the FIP1L1-PDGFRA fusion gene itself
could be expressed in tumors from other tissue types. This
hypothesis can be tested using modern techniques for high-density
comparative genomic hybridization, among other strategies, to
search for subcytogenetic deletions in the 5⬘ flanking region of all
known receptor tyrosine kinases. It is also possible that small
interstitial deletions can engender gain-of-function oncogenes
involving other classes of genes. Efforts to identify such deletions
in all tumor types is warranted, in part because there are convincing
data that gain-of-function fusion proteins are candidates for
molecularly targeted therapies such as imatinib.
One patient who initially responded to imatinib relapsed with an
acquired T674I substitution in the PDGFR␣ kinase domain of the
FIP1L1-PDGFRA fusion. The mutation confers resistance to
imatinib in vitro and in vivo.3,179 Development of resistance due to
point mutation is not unexpected given the experience with
imatinib in therapy of CML and CML blast crisis. We hypothesized
that selective small-molecule inhibitors of PDGFR␣ that have a
different chemical structure than imatinib might be able to overcome resistance to imatinib in this context. We have demonstrated
that an alternative PDGFR␣ inhibitor, PKC412, is an effective
inhibitor of the imatinib-resistant FIP1L1-PDGFR␣ T674I mutant
both in vitro and in vivo.179 These observations provide proof of
principle that one strategy to preclude or overcome resistance
mutations may be to use combinations of selective tyrosine kinase
inhibitors that do not have overlapping toxicities.
The basis for the apparent lineage predilection of FIP1L1PDGFR␣ for eosinophils is not well understood. No data have been
reported regarding expression of FIP1L1 in eosinophils from
healthy individuals. The FIP1L1-PDGFRA fusion has been detected in enriched eosinophils, neutrophils, and mononuclear cells
by FISH and reverse transcriptase–polymerase chain reaction
(RT-PCR) in a patient with a diagnosis of systemic mast cell
disease and eosinophilia, consistent with acquisition of the rearrangement in an early hematopoietic progenitor.176 It is possible
that it is present in all myeloid lineages but that eosinophils are
particularly sensitive to the FIP1L1-PDGFR␣ proliferative signal.
Data that would support this include neutrophilia observed in many
HES patients and elevated tryptase indicative of mast cell involvement.175 It will also be important to evaluate lymphoid lineage
involvement of FIP1L1-PDGFRA, especially in those patients with
T-cell clonality associated with HES. Each of these questions can
be addressed with the molecular tools now in hand.
The presence of the FIP1L1-PDGFRA fusion gene as a
consequence of deletion can be used both to predict response to
imatinib and to monitor response to therapy. We have developed
sensitive RT-PCR–based assays for this purpose as well as FISH
probes to reliably detect the deletion (Figure 2B-C). In a recent
report, molecular remission was documented by PCR testing of the
BLOOD, 15 APRIL 2004 䡠 VOLUME 103, NUMBER 8
peripheral blood in 5 of 6 patients diagnosed with HES-MPD after
1 to 12 months of 400 mg imatinib daily.
Implications of FIP1L1-PDGFRA for the
diagnosis, classification, and treatment of
eosinophilic disorders
Diagnosis and classification
In the WHO classification, eosinophil clonality or the presence of
another clonal marker distinguishes CEL from HES.10 However,
the report by Cools et al3 indicates that FIP1L1-PDGFRA gene
fusions can be identified in both HES and CEL patients, in
contradistinction to their WHO classification as separate disorders.10 In light of these findings, a reappraisal of the WHO scheme
for these eosinophilic diseases may ultimately be warranted. Given
the early state of knowledge about FIP1L1-PDGFRA, any attempt
at classification at this time would be considered preliminary,
because additional data on prevalence, clinicopathologic correlates, and genetics will be important. However, based on available
information, a tentative schema can be considered to help with
clinical decision making and to provide a platform for addressing
critical questions regarding classification.
It may be useful to consider the implications of the FIP1L1PDGFRA fusion within a recently proposed framework that
classifies blood eosinophilia as reactive, clonal, and HES.15 One
possible approach for evaluating hypereosinophilia in the context
of the FIP1L1-PDGFRA discovery is presented in Figure 4. In
patients whose workup is negative for secondary causes of
eosinophilia, screening for the FIP1L1-PDGFRA gene fusion
could subsequently be undertaken using either RT-PCR or interphase/metaphase FISH. Patients positive for the fusion (and with
fewer than 20% marrow blasts) could be classified into one clonal
category of blood eosinophilia, “FIP1L1-PDGFRA–positive chronic
eosinophilic leukemia” (F-P⫹ CEL, Figure 4A). Similar to cases of
BCR-ABL–positive CML, F-P⫹ CEL patients would be predicted to
have a high hematologic response rate to imatinib. Based on the
limited number of patients evaluated, this group currently accounts
for 50% to 60% of all HES/CEL cases. However, a more accurate
estimate of the proportion of F-P⫹ CEL patients will require
screening larger numbers of individuals with idiopathic hypereosinophilia. The recent description of the FIP1L1-PDGFRA fusion in
3 patients with a diagnosis of SM and eosinophilia indicates that
the fusion may occur in a spectrum of clonal bone marrow
disorders associated with eosinophilia and may not strictly define a
subset of chronic eosinophilic leukemias per se. New classifications will need to reconcile such genotype-phenotype variations
among patients positive for the FIP1L1-PDGFRA fusion.
Patients without reactive eosinophilia and a negative screen for
the FIP1L1-PDGFRA gene fusion could be potentially categorized
into 1 of at least 3 diagnostic groups (Figure 4A). FIP1L1PDGFRA–negative patients with a clonal cytogenetic abnormality,
clonal eosinophils, or increased marrow blasts (5%-19%) could be
categorized as “CEL, unclassified.” FIP1L1-PDGFRA–negative
patients without any of these clonal features or without increased
marrow blasts could be assigned to the diagnostic group “HES.” A
third group, designated “T-cell–associated HES,” would consist of
HES patients in whom an abnormal T-cell population is demonstrated. Such diagnostic groups may not be mutually exclusive in
all cases. Instances may arise in which CEL patients with the
FIP1L1-PDGFRA fusion have another clonal marker and/or an
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FIP1L1-PDGFRA IN HYPEREOSINOPHILIC SYNDROME
2887
indicative of clonal molecular abnormalities besides FIP1L1PDGFRA. In such cases, an effort should be made to identify
alternate targets of imatinib that contribute to the pathogenesis of
these diseases.
Conclusion
Figure 4. Possible diagnostic and treatment algorithm for hypereosinophilia.
(A) Patients whose workup is negative for secondary causes of eosinophilia
subsequently undergo testing for the FIP1L1-PDGFRA gene fusion. Patients positive
for the fusion are classified as having one category of FIP1L1-PDGFRA–positive
(F-P⫹) clonal eosinophilia (eg, F-P⫹ chronic eosinophilic leukemia [CEL] or F-P⫹
systemic mastocytosis [SM] with eosinophilia). A negative test for the fusion would
classify patients into 1 of 3 diagnostic groups based on additional laboratory criteria:
CEL, unclassified; hypereosinophilic syndrome (HES); or T-cell–associated HES. (B)
A trial of imatinib is recommended for FIP1L1-PDGFRA–positive CEL or SM patients.
Conventional therapy or a trial of imatinib could be attempted for symptomatic
FIP1L1-PDGFRA–negative patients. FIP1L1-PDGFRA–negative patients who demonstrate hematologic remissions with imatinib could be placed in a provisional
category of imatinib-responsive (IR), warranting investigation of potential alternative
targets of imatinib in these cases.
abnormal population of T cells. For example, 2 patients in the study
by Cools et al exhibited both the FIP1L1-PDGFRA fusion and
clonal cytogenetic abnormalities.3 It is also possible that some
patients with T-cell–mediated HES could have a FIP1L1-PDGFRA
fusion involving both the myeloid and lymphoid lineage. It will be
of particular interest to analyze those patients with T-cell–mediated
HES that progress to T-cell lymphoma or Se´ zary syndrome.
Treatment
The in vitro and in vivo data reported by Cools et al support the use
of imatinib in FIP1L1-PDGFRA–positive patients.3 Four of 9
patients exhibiting complete hematologic responses to imatinib had
no detectable FIP1L1-PDGFRA gene fusion.3 Therefore, in addition to conventional therapy, a trial of imatinib could have
therapeutic value in some of these symptomatic FIP1L1-PDGFRA–
negative patients (eg, CEL, unclassified; or HES). The efficacy of
imatinib in a cytokine-driven disease such as T-cell–associated
HES has not yet been reported and requires investigation.
From a broader research perspective, it could also be useful to
provisionally categorize FIP1L1-PDGFRA–negative patients with
hematologic responses to imatinib as “imatinib-responsive” (IR)
(Figure 4B). Imatinib responsiveness in these patients may be
Imatinib’s efficacy in patients with HES and CEL has led to the
identification of FIP1L1-PDGFR␣ as a pathogenetically relevant
tyrosine kinase. These findings serve as a platform for new avenues
of research that may translate into improved biologic and clinical
characterization of these eosinophilic diseases. Future investigations should attempt to address the molecular basis for the response
to imatinib in FIP1L1-PDGFRA–negative patients and how the
constitutively activated FIP1L1-PDGFR␣ kinase contributes to the
phenotype of hypereosinophilia, similar to oncogenic fusions
involving PDGFR␤ in a subset of chronic MPDs. It will also be of
interest to evaluate how the expression and function of the fusion
differ between eosinophils and other cell lineages. One means of
addressing this latter question is to study imatinib’s effects on the
proliferation, differentiation, survival, and intracellular signaling of
eosinophils or other enriched myeloid or lymphocyte populations
derived from patients with the FIP1L1-PDGFRA fusion.
Studies are ongoing to further characterize hematologic and
clinical responses among FIP1L1-PDGFRA–positive patients and
the extent to which imatinib can elicit molecular remissions and
cytogenetic responses in individuals with abnormal karyotypes.
Similar to CML, it will be important to evaluate the maximally
effective doses of imatinib needed to achieve these end points
because suboptimal dosing may adversely impact response rates
and the patterns of resistance that emerge.
In their 1994 Blood review, Weller and Bubley indicated that the
goal of therapy for HES patients, particularly those with apparent
chronic nonmalignant disease, should be control of organ damage
rather than simple suppression of asymptomatic eosinophilia.21
This prevailing paradigm will require reappraisal in the subset of
HES patients with FIP1L1-PDGFRA. It will be of great interest to
ascertain whether early treatment of fusion-positive patients with
asymptomatic hypereosinophilia can forestall the development of
organ disease and increase disease-free and overall survival.
Screening of archival specimens for the FIP1L1-PDGFRA fusion
will allow comparison of the natural history of HES in conventionally treated patients with those enrolled in future studies evaluating
the efficacy of imatinib. These new biologic and clinical data will
provide a useful framework that clinicians, pathologists, and
molecular biologists can use to develop improved classification
guidelines and algorithms for the diagnosis and treatment of these
eosinophilic disorders.
Acknowledgments
We thank Dr Iwona Wlodarska, Center for Human Genetics,
Leuven, Belgium, for kindly providing the FISH image in Figure 2.
We also gratefully acknowledge collaborating physicians and
investigators for their participation in the clinical and biologic
characterization of patients, Kathleen Dugan and Lenn Fechter for
their assistance in patient care, Rhoda Falkow for tissue banking of
clinical specimens, and patients for their participation in studies of
imatinib in HES. J.G. also recognizes Dr Peter Greenberg for his
valuable mentorship on the NIH K23HL04409 grant.
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GOTLIB et al
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Erratum
In the article by Abroun et al entitled “Receptor synergy of interleukin-6 (IL-6)
and insulin-like growth factor-I that highly express IL-6 receptor ␣ myeloma
cells,” which appeared in the March 15, 2004, issue of Blood (Volume
103:2291-2298), the article title should have read “Receptor synergy of
interleukin-6 (IL-6) and insulin-like growth factor-I in myeloma cells that
highly express IL-6 receptor ␣.”
This title error was corrected online in departure from print.