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Mayo Clin Proc. 2005;80:75-83 © 2005 Mayo Foundation for Medical Education and Research  
http://www.mayoclinicproceedings.com/inside.asp?AID=821&UID=3926  

REVIEW

Blood Eosinophilia: A New Paradigm in Disease Classification, Diagnosis, and Treatment

From the Department of Internal Medicine and Division of Hematology, Mayo Clinic College of Medicine, Rochester, Minn.
AYALEW TEFFERI, MD

Address reprint requests and correspondence to Ayalew Tefferi, MD, Division of Hematology, Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN 55905 (e-mail: tefferi.ayalew@mayo.edu).

Abstract

Acquired blood eosinophilia is considered either a primary or a secondary phenomenon. Causes of secondary (ie, reactive) eosinophilia include tissue-invasive parasitosis, allergic or inflammatory conditions, and malignancies in which eosinophils are not considered part of the neoplastic process. Primary eosinophilia is classified operationally into 2 categories: clonal and idiopathic. Clonal eosinophilia stipulates the presence of either cytogenetic evidence or bone marrow histological evidence of an otherwise classified hematologic malignancy such as acute leukemia or a chronic myeloid disorder. Idiopathic eosinophilia is a diagnosis of exclusion (ie, not secondary or clonal). Hypereosinophilic syndrome is a subcategory of idiopathic eosinophilia; diagnosis requires documentation of both sustained eosinophilia (absolute eosinophil count =1500 cells/µL for at least 6 months) and target organ damage (eg, involvement of the heart, lung, skin, or nerve tissue). Genetic mutations involving the platelet-derived growth factor receptor genes (PDGFR-a and PDGFR-ß) have been pathogenetically linked to clonal eosinophilia, and their presence predicts treatment response to imatinib. Accordingly, cytogenetic and/or molecular investigations for the presence of an imatinibsensitive molecular target should accompany current evaluation for primary eosinophilia. In the absence of such a drug target, specific treatment is dictated by the underlying hematologic malignancy in cases of clonal eosinophilia; however, the initial treatment of choice for symptomatic patients with hypereosinophilic syndrome is prednisone and/or interferon alfa.

Mayo Clin Proc. 2005;80(1):75-83

AEC = absolute eosinophil count; CEL = chronic eosinophilic leukemia; CML = chronic myeloid leukemia; CMML = chronic myelomonocytic leukemia; FGFR1 = fibroblast growth factor receptor 1; FISH = fluorescence in situ hybridization; HES = hypereosinophilic syndrome; IL = interleukin; MPD = myeloproliferative disorder; PDGFR = platelet-derived growth factor receptor; SM = systemic mastocytosis; SM-eos = SM associated with prominent blood eosinophilia 

Eosinophils are derived from hematopoietic stem cells that are committed initially to the myeloid and subsequently to the basophil-eosinophil granulocyte lineage.1 As depicted in Figure 1, the mature eosinophil, when examined by standard blood-staining techniques, displays a bilobed nucleus and an abundant cytoplasm filled with reddish-orange granules. The material in these granules includes cationic proteins (major basic protein, eosinophilic cationic protein, eosinophil-derived neurotoxin, eosinophil peroxidase), cytokines (interleukins [ILs], tumor necrosis factor), and lipid mediators (leukotriene C4).2 Interleukin 5 is considered the major eosinophil growth and survival factor, whereas chemokines (eotaxin, platelet-activating factor, RANTES [regulated on activation, normal T expressed and secreted]) and endothelial adhesion molecules (integrins, vascular cell adhesion molecules) contribute to eosinophil trafficking.3-5

Major basic protein, eosinophil cationic protein, and eosinophil-derived neurotoxin are the primary mediators of eosinophil-associated toxicity to microbes (parasites, protozoa, bacteria, viruses) and human tissue (myocarditis, pneumonitis, dermatitis, neuropathy, vasculitis).6-16 The lung and gastrointestinal systems constitute the main residence for eosinophils. Blood eosinophilia (absolute eosinophil count [AEC] =600 cells/µL) is the usual initial clue for the presence of an eosinophilic disorder. The degree of blood eosinophilia, in the absence of active treatment, can be categorized into mild (AEC 600-1500 cells/µL), moderate (AEC 1500-5000 cells/µL), or severe (AEC >5000 cells/µL).17 Target organ damage is unusual with mild eosinophilia, but its occurrence in association with moderate to severe eosinophilia does not appear to depend on the specific cause of eosinophilia (ie, in addition to the well-established association of target organ damage with primary eosinophilia, it also has been reported to occur in both familial and secondary eosinophilia).18,19

GENERAL CLASSIFICATION OF EOSINOPHILIC DISORDERS

Blood eosinophilia can be classified as either familial or acquired (Table 1). Acquired eosinophilia is classified further into a primary or a secondary process, depending on whether eosinophils are considered integral to the underlying disease. Infectious causes and noninfectious causes of secondary eosinophilia (Table 1) are prevalent in underdeveloped and developed countries, respectively. Primary eosinophilia occurs primarily in males and is considered clonal in the presence of either cytogenetic evidence or bone marrow histological evidence of an otherwise defined neoplastic hematologic disorder. Otherwise, a working diagnosis of idiopathic eosinophilia is made, and in the presence of both sustained eosinophilia (AEC =1500 cells/µL for at least 6 months) and target organ damage (eg, skin, heart, lung, nerve tissue), the process is subclassified as hypereosinophilic syndrome (HES).20

eosinophilia_cell.jpg

FIGURE 1. Peripheral blood smear shows an eosinophil (E), basophil (B), and other blood cells (image courtesy of Chin-Yang Li, MD, Department of Laboratory Medicine and Pathology, Division of Hematopathology, Mayo Clinic, Rochester, Minn).

TABLE 1. Classification and Causes of Blood Eosinophilia*

*CTD = connective tissue disease; HES = hypereosinophilic syndrome; PDGFR = platelet-derived growth factor receptor.

PATHOGENESIS AND CLINICAL MANIFESTATIONS

FAMILIAL EOSINOPHILIA

Familial eosinophilia is rare, and its genetic basis, at least in some cases, may be similar to that of clonal eosinophilia.18,21 In such cases, the chromosomal region 5q31-33 has been identified as the “hot zone,” although it may not involve mutations of some of the resident genes responsible for the synthesis of known eosinophil growth factors including IL-3, IL-5, and granulocyte-macrophage colony-stimulating factor.22 Interestingly, one recently reported familial case involved a translocation-associated mutation of the platelet-derived growth factor receptor gene PDGFRB, which is known to reside in the 5q31-33 chromosomal region and to be pathogenetically linked to some cases of clonal eosinophilia.21,23 In general, familial eosinophilia is an extremely rare autosomal dominant disorder that is characterized by a stable eosinophil count and, compared with HES, a lesser degree of eosinophil activation as well as a more benign clinical course.24

ACQUIRED EOSINOPHILIA

Secondary Eosinophilia.

The most common cause of secondary eosinophilia is tissue-invasive parasitosis including schistosomiasis, visceral toxocariasis, strongyloidiasis, filariasis, ancylostomiasis, fascioliasis, trichinellosis, and paragonimiasis (Table 1).25-32 In general, parasites that are isolated in either the intestinal lumen (Cestoda, Ascaris) or an intact cyst (Echinococcus granulosus) do not cause blood eosinophilia unless they are introduced systemically through tissue invasion or cyst disruption.33 In addition to helminths, some (Toxoplasma gondii, Dientamoeba fragilis, Isospora belli) but not other (Giardia lamblia, Entamoeba histolytica) protozoan infections may induce blood eosinophilia.33-35 Rare reports of eosinophilia-associated bacterial (borrelia) or viral (human immunodeficiency virus) infections have been published.36,37

Noninfectious causes of secondary eosinophilia include drugs (sulfa derivatives, gold compounds, carbamazepine, myeloid growth factors, purine nucleoside analogues),38,45 toxins (associated with eosinophilia-myalgia syndrome, toxic oil syndrome, toxic shock syndrome),46,48 allergic disorders (asthma, hay fever, atopic dermatitis, allergic bronchopulmonary aspergillosis),49-51 idiopathic/autoimmune inflammatory conditions (granulomatous and/or systemic vasculitis, Churg-Strauss syndrome, Wegener granulomatosis, Kimura disease, angiolymphoid hyperplasia with eosinophilia, bullous pemphigoid and other cutaneous disorders, eosinophilic fasciitis, systemic sclerosis or scleroderma, polyarteritis, sarcoidosis, inflammatory bowel disease), malignancies in which eosinophils are not considered part of the neoplastic clone (Hodgkin and non-Hodgkin lymphoma, metastatic cancer),52-57 and endocrinopathies including Addison disease (Table 1).58 Secondary eosinophilia in inflammatory and malignant conditions is mediated by tissue-derived or tumor-derived eosinophilogenic cytokines.56,57,59-61

Primary Eosinophilia.

Clonal Eosinophilia.

A diagnosis of clonal eosinophilia requires the presence of either cytogenetic evidence or bone marrow morphologic evidence for either acute leukemia or a chronic myeloid disorder (Table 1). Hematologic disorders that can be accompanied by clonal eosinophilia include acute myeloid leukemia,62 acute lymphocytic leukemia,63 chronic myeloid leukemia (CML),64 myelodysplastic syndrome,65 and both classic and atypical cases of myeloproliferative disorders (MPDs).66,67 The atypical MPD category includes chronic eosinophilic leukemia (CEL),68 systemic mastocytosis (SM),69 and chronic myelomonocytic leukemia (CMML).70 Recent developments in the molecular characterization of pathogenesis, in a subset of patients with clonal eosinophilia, have identified activating mutations of 3 receptor tyrosine kinase genes: PDGFRA, PDGFRB, and fibroblast growth factor receptor 1 (FGFR1).71

Within the context of hematologic malignancies, PDGFRA mutations have been connected so far with a subset of patients with SM associated with prominent blood eosinophilia (SM-eos).72-76 In general, SM-eos makes up approximately 20% of all cases of SM in adults.77 Of these cases of SM-eos, approximately half may be associated with a specific PDGFRA mutation caused by an 800 kilobase interstitial deletion involving chromosome 4q12, resulting in juxtaposition of PDGFRA and FIP1L1 genes (FIP1L1-PDGFRA).74,75 The fusion gene generates a constitutively activated PDGFRA tyrosine kinase that transforms hematopoietic cells.75 Other cases of SM-eos are associated with a C-kit mutation.74 Systemic mastocytosis not associated with eosinophilia does not display the FIP1L1-PDGFRA mutation.75 Although rare, PDGFRA also may be activated through chromosomal translocations as in t(4;22)(q12;q11).76

Patients with FIP1L1-PDGFRA+ SM-eos display a “myeloproliferative” clinical phenotype with organomegaly, cytopenia, increased serum B12 levels, and bone marrow hypercellularity with myelofibrosis.75,78,79 As a result, investigators use the terms myeloproliferative-variant HES78 and FIP1L1-PDGFRA+CEL79 to describe the same disease. However, most, if not all, such patients display bone marrow mast cell infiltration with morphologically and immunophenotypically abnormal mast cells.72,73 Regardless, the term FIP1L1-PDGFRA+eosinophilic disorder could be used to avoid confusion.73 Patients with FIP1L1-PDGFRA+ eosinophilic disorder also are characterized by a high risk of eosinophilic heart disease and inferior survival compared with those with FIP1L1-PDGFRA– clonal eosinophilia.75,79

The PDGFRB gene is located on chromosome 5q33, and its activation through translocation to various partner chromosomes, including t(5;12)(q33;p13), t(5;10)(q33;q21), t(5;7)(q33;q11.2), t(5;14)(q33;q13), t(5;17)(q33;p11), and t(1;5)(q23;q33), produces a distinct MPD that usually is associated with prominent eosinophilia and sometimes with monocytosis.23,66,80 Pathologic diagnosis in previously described cases of PDGFRB+ clonal eosinophilia have included CEL, atypical CML or MPD, and CMML.81-83

The gene for FGFR1 is located on chromosome 8p11, and its activation through translocation to different chromosome partners, including t(8;13)(p11;q12), t(8;9)(p11;q33), t(6;8)(q27;p11), and t(8;22)(p11;q22), produces a myeloproliferative syndrome with eosinophilia, lymphadenopathy, and a high incidence of T-cell non-Hodgkin lymphoma with progression to acute myeloid leukemia.84 Other karyotypic variants involving FGFR1, including t(8;17)(p11;q25), t(8;11)(p11;p15), t(8;12)(p11;q15), and ins(12;8)(p11;p11; p21), have been associated with SM, acute leukemia, or MPD associated with both T-cell lymphoma and marrow eosinophilia.85

Idiopathic Eosinophilia.

When both clinical and laboratory evaluations do not clearly identify either a secondary or a clonal cause, a working diagnosis of idiopathic eosinophilia is reasonable. For now, HES is considered a subcategory of idiopathic eosinophilia that requires documentation of both target organ damage and an AEC of 1500 cells/µL or greater for at least 6 months.20,86 Several review articles have described the clinical manifestations and natural history of HES.20,86,88 These and other case reports have shown that some cases evolve into either acute leukemia or an aggressive disease phenotype that is indistinguishable from an MPD.89-91 This information has long suggested that HES may represent a clonal hematologic disorder. This contention was supported by clonality studies that used X-linked DNA analysis.92 In contrast, the presence of clonal TH2 lymphocytes in a subset of patients with “HES” suggests a pathogenetic heterogeneity that may include an IL-5–mediated secondary eosinophilia in the mix.93,94 In a study of 60 patients with HES, 16 (27%) had T cells with an aberrant immunophenotype, and T-cell clonality was suggested in half of these 16 patients.95

As in clonal eosinophilia, more than 90% of patients with HES are males. The reason for male predominance in HES and in clonal eosinophilia is unknown. Clinical manifestations can be either nonspecific (cough, nocturnal sweating, fatigue, anorexia, weight loss, gastrointestinal symptoms)96 or directly related to an affected target organ including the skin (pruritus, erythematous papules, nodules, urticaria, angioedema, mucosal ulcers, eosinophilic cellulitis or Wells syndrome),97-99 heart (mural thrombus, endocardial fibrosis, cardiomyopathy, elevated serum troponin level),86,100,101 nervous system (sensory and motor neuropathy, mononeuritis multiplex, isolated vasculitis of central nervous system, eosinophilic meningitis, transverse myelitis),102-105 lung (pulmonary infiltrates, lung nodules, acute respiratory distress syndrome),106-108 or gastrointestinal system (gastroenteritis, inflammatory bowel disease, sclerosing cholangitis).109-112 Thromboembolic complications, including Budd-Chiari syndrome, are not infrequent in HES,96,113,114 and in isolated reports, HES has been associated with retinal vein occlusions, polymyositis, arthritis, and renal disease.115-118

DIAGNOSIS

A thorough patient history is the most important part of the evaluation for blood eosinophilia, and it should guide the extent and type of laboratory tests performed. The initial focus should be on international travel history and a review of current and recent medications. In the absence of possible drug association, a stool test should be performed in all cases to look for ova and larvae of intestinal worms (ascaris, schistosoma, ancylostoma, cestodes, fasciola, strongyloides). Next, depending on the travel history, the following tests and procedures should be performed: urine sediment tests (schistosoma), blood concentration tests (filaria), serology (strongyloides, filaria, trichinosis, visceral larva migrans, schistosomiasis), sputum examination (paragonimiasis, visceral larva migrans), chest radiography (paragonimiasis, ascariasis), computed tomography (echinococcus, cysticercosis), small bowel biopsy (isosporiasis, strongyloidosis), or muscle biopsy (trichinosis). However, work-up beyond stool examination is recommended only if history dictates. Similarly, a good history and basic laboratory tests should be adequate to address the possibility of a noninfectious cause of secondary eosinophilia, and only in the presence of historical clues should more invasive and costly interventions be pursued.

All patients with suspected primary eosinophilia should undergo bone marrow examination with cytogenetics. Also, my colleagues and I encourage use of bone marrow immunohistochemical stains for tryptase and mast cell immunophenotyping (neoplastic but not normal or reactive mast cells express CD25) to test for SM. The following PDGFRB rearrangements currently are detected by conventional cytogenetics: t(5;12)(q33;p13), t(5;10)(q33;q21), t(5;7)(q33;q11.2), t(5;14)(q33;q13), t(5;17)(q33;p11), and t(1;5)(q23;q33). In contrast, standard cytogenetic methods do not detect the usual PDGFRA rearrangement that is a result of an interstitial 4q12 deletion. This must be sought with either a fluorescence in situ hybridization (FISH)–based or a reverse transcriptase polymerase chain reaction–based laboratory technique.73 At present, we perform 3 laboratory tests (bone marrow biopsy, bone marrow cytogenetics, peripheral blood FISH for FIP1L1-PDGFRA) in all patients with primary eosinophilia because of the important therapeutic implications (Figure 2).

Finally, in addition to looking for the cause of eosinophilia, laboratory tests to assess possible eosinophilic tissue damage may be required and include echocardiography, chest radiography, pulmonary function tests, and, in the presence of symptoms, tissue biopsy.

TREATMENT OF PRIMARY EOSINOPHILIA

CLONAL EOSINOPHILIA

In general, the underlying hematologic malignancy dictates treatment in clonal eosinophilia. In acute leukemia, for example, standard induction chemotherapy is used.119 In CML, imatinib is the drug of choice.120 Imatinib works in CML by inhibiting the leukemogenic bcr-abl gene product, which is a constitutively activated Abl tyrosine kinase.121-123 Although relatively selective in its action, imatinib inhibits other receptor tyrosine kinases including PDGFR and Kit.124,125 The mechanism of action involves a competitive occupation of an adenosine triphosphate–binding site of the catalytic domain of the kinase by a conformation-dependent mechanism.126

The in vitro demonstration of imatinib-induced inhibition of both PDGFR- and Kit-associated signal transduction formed the rationale for using the drug in clonal eosinophilia associated with SM (SM-eos). This is because (1) Kit ligand and Kit-associated signaling are key for the growth and development of human mast cells127 and (2) approximately 50% of patients with SM-eos may carry a constitutively activated PDGFRA mutation, as discussed previously.72,75 In vitro, imatinib effectively inhibits normal mast cell growth and development128 as well as the growth of human mast cell lines and primary cells that carry certain (Val560Gly) but not other (Asp816Val) c-kit mutations.129,130

Consistent with these in vitro observations, imatinib has been shown effective in a subset of patients with SM-eos who carry the FIP1L1-PDGFRA mutation but not the c-kit Asp816Val mutation.131 Patients with SM-eos and the FIP1L1-PDGFRA mutation experience both molecular and mast cell immunophenotypic remissions with relatively low doses of imatinib (100 mg/d).74,132 Other investigators refer to FIP1L1-PDGFRA+ SM-eos as either myeloproliferative-variant HES, FIP1L1-PDGFRA+ CEL, or FIP1L1-PDGFRA+ HES and have reported equally impressive imatinib treatment results.75,78,79,133-135 Imatinib therapy produces complete clinical, pathologic, and molecular remissions in clonal eosinophilia connected with PDGFRB mutations that are usually associated with a chronic myeloid disorder that phenotypically resembles CEL, CMML, or atypical MPD.66,82,136

FIGURE 2. A diagnostic and treatment algorithm for blood eosinophilia. FISH = fluorescence in situ hybridization; RT-PCR = reverse transcriptase polymerase chain reaction.

IDIOPATHIC EOSINOPHILIA INCLUDING HES

Most patients with symptomatic HES respond to prednisone alone or in combination with hydroxyurea.137,138 Patients with HES refractory to corticosteroids have been reported to respond to cyclosporine,139 vincristine,140,141 interferon alfa,142-144 cladribine,141,145 or etoposide.146 My preference during symptomatic disease is to use interferon alfa early either by itself or combined with low doses of prednisone. For patients in whom first-line treatment with corticosteroids, hydroxyurea, and interferon alfa fails, the choice of second-line treatment is currently arbitrary, and any of the aforementioned agents can be used before an aggressive approach such as allogeneic hematopoietic stem cell transplantation is considered seriously. Because of the documentation of imatinib-induced partial remissions in approximately 50% of patients with true HES (ie, FIP1L1-PDGFRA–), it is reasonable to try the specific drug as a second-line therapy.75 However, it should be noted that patients with true HES are unlikely to respond to low-dose imatinib (100 mg/d), and a higher dose of the drug (400 mg/d) should be used in this instance (Figure 2). In patients with HES refractory to drugs, both myeloablative and non-myeloablative allogeneic hematopoietic stem cell transplantation have been used successfully and can be considered.147-150 Currently, the role of novel drug treatment approaches to HES, including the use of imatinib75,78,79 and monoclonal antibodies to either IL-5151-153 or CD52 (alemtuzumab),154 is being defined.

CURRENT ALGORITHM FOR THE DIAGNOSIS AND TREATMENT OF EOSINOPHILIC DISORDERS

Figure 2 outlines a proposed algorithm for the diagnosis and treatment of eosinophilic disorders. To begin treatment of a patient with blood eosinophilia, the possibility of secondary eosinophilia must be excluded. Once this is accomplished, I recommend obtaining a set of blood and bone marrow studies. The blood studies should include serum tryptase (an increased level suggests SM), T-cell receptor gene rearrangement analysis (positive test results suggest an underlying clonal T-cell disorder), and serum IL-5 (an elevated level requires careful evaluation of bone marrow studies and T-cell gene rearrangement studies for the presence of a clonal T-cell disease). Bone marrow examination should include cytogenetic studies, tryptase immunostains, and FISH or reverse transcriptase polymerase chain reaction to screen for FIP1L1-PDGFRA. The last-mentioned test also can be performed on peripheral blood.

If this work-up reveals an imatinib-sensitive molecular target (PDGFRA or PDGFRB mutations), then treatment with low-dose imatinib (100 mg/d) is recommended, and a complete and durable remission can be expected. We currently recommend an initial imatinib dosage of 100 mg/d for FIP1L1-PDGFRA+ clonal eosinophilia because this specific dosage, as discussed previously, has been associated with molecular disease remission.73 It is reasonable to consider treatment even in the absence of symptoms for FIP1L1-PDGFRA+ clonal eosinophilia in hopes of preventing serious cardiovascular complications that may or may not be amenable to imatinib therapy once they occur.78,155

In the absence of an imatinib-sensitive molecular target, the physician first must decide whether treatment is indicated and if so, choose a first-line treatment that is suitable for the underlying clonal process or, in cases of HES, treat with interferon alfa and/or prednisone. Imatinib is unlikely to benefit patients with clonal eosinophilia who do not have a known drug-sensitive mutation. Similarly, although some patients with true HES experience partial remission with imatinib therapy at 400 mg/d,72 the long-term benefit of single-agent imatinib therapy in FIP1L1-PDGFRA– HES is unknown. Finally, we and others have described life-threatening cardiogenic shock associated with imatinib therapy for HES.156,157 Fortunately, this potentially fatal complication responds well to systemic corticosteroid therapy and may be predicted by elevated serum troponin levels before treatment.157 For patients with either baseline elevation of serum troponin level or echocardiographic evidence for eosinophilic heart disease, we recommend concomitant prednisone therapy (1 mg/kg) during the first week of treatment with imatinib. Prednisone can be tapered during the second week of therapy.

CONCLUSION

The clinical observation158 that some patients with “HES” responded to treatment with imatinib, which is a small molecule inhibitor of certain receptor tyrosine kinases,73 led to the recent discovery of the association between blood eosinophilia and a cytogenetically occult genetic mutation (FIP1L1-PDGFRA).75 Such molecular characterizations may ultimately result in HES becoming a nonentity in the spectrum of primary eosinophilic disorders. More importantly, the identification of disease-causing mutations is an essential step toward the development and application of rational drug therapy. At present, approximately 10% to 20% of patients with primary eosinophilia are known to harbor a molecular target that predicts an excellent response to imatinib therapy.72,73 However, a subset of patients with HES without known imatinib targets also has been reported to respond to the drug.73,75 These observations raise the exciting prospect of discovering new drug targets in eosinophilic disorders as well as future therapeutic successes with the use of second-generation kinase inhibitors that are more potent than imatinib and have a broader spectrum of activity.159,160

REFERENCES

  1. Denburg JA, Telizyn S, Messner H, et al. Heterogeneity of human peripheral blood eosinophil-type colonies: evidence for a common basophileosinophil progenitor. Blood. 1985;66:312-318.
  2. Rothenberg ME.  Eosinophilia. N Engl J Med. 1998;338:1592-1600.
  3. Yamaguchi Y, Hayashi Y, Sugama Y, et al. Highly purified murine interleukin 5 (IL-5) stimulates eosinophil function and prolongs in vitro survival: IL-5 as an eosinophil chemotactic factor. J Exp Med. 1988;167:1737-1742.
  4. Elsner J, Kapp A.  The chemokine network in eosinophil activation. Allergy Asthma Proc. 2001;22:139-148.
  5. Dobrina A, Menegazzi R, Carlos TM, et al. Mechanisms of eosinophil adherence to cultured vascular endothelial cells: eosinophils bind to the cytokine-induced ligand vascular cell adhesion molecule-1 via the very late activation antigen-4 integrin receptor. J Clin Invest. 1991;88:20-26.
  6. Gleich GJ, Adolphson CR, Leiferman KM.  The biology of the eosinophilic leukocyte. Annu Rev Med. 1993;44:85-101.
  7. Hamann KJ, Gleich GJ, Checkel JL, Loegering DA, McCall JW, Barker RL.  In vitro killing of microfilariae of Brugia pahangi and Brugia malayi by eosinophil granule proteins. J Immunol. 1990;144:3166-3173.
  8. Lehrer RI, Szklarek D, Barton A, Ganz T, Hamann KJ, Gleich GJ.  Antibacterial properties of eosinophil major basic protein and eosinophil cationic protein. J Immunol. 1989;142:4428-4434.
  9. Torpier G, Colombel JF, Mathieu-Chandelier C, et al. Eosinophilic gastroenteritis: ultrastructural evidence for a selective release of eosinophil major basic protein. Clin Exp Immunol. 1988;74:404-408.
  10. Tai PC, Ackerman SJ, Spry CJ, Dunnette S, Olsen EG, Gleich GJ.  Deposits of eosinophil granule proteins in cardiac tissues of patients with eosinophilic endomyocardial disease. Lancet. 1987;1:643-647.
  11. Slifman NR, Loegering DA, McKean DJ, Gleich GJ.  Ribonuclease activity associated with human eosinophil-derived neurotoxin and eosinophil cationic protein. J Immunol. 1986;137:2913-2917.
  12. Young JD, Peterson CG, Venge P, Cohn ZA.  Mechanism of membrane damage mediated by human eosinophil cationic protein. Nature. 1986;321:613-616.
  13. Sorrentino S, Glitz DG, Hamann KJ, Loegering DA, Checkel JL, Gleich GJ.  Eosinophil-derived neurotoxin and human liver ribonuclease: identity of structure and linkage of neurotoxicity to nuclease activity. J Biol Chem. 1992;267:14859-14865.
  14. Sunohara N, Furukawa S, Nishio T, Mukoyama M, Satoyoshi E.  Neurotoxicity of human eosinophils towards peripheral nerves. J Neurol Sci. 1989;92:1-7.
  15. Chen KR, Su WP, Pittelkow MR, Conn DL, George T, Leiferman KM.  Eosinophilic vasculitis in connective tissue disease. J Am Acad Dermatol. 1996;35(2, pt 1):173-182.
  16. Shah AM, Brutsaert DL, Meulemans AL, Andries LJ, Capron M.  Eosinophils from hypereosinophilic patients damage endocardium of isolated feline heart muscle preparations. Circulation. 1990;81:1081-1088.
  17. Brito-Babapulle F.  The eosinophilias, including the idiopathic hypereosinophilic syndrome. Br J Haematol. 2003;121:203-223.
  18. Lin AY, Nutman TB, Kaslow D, et al. Familial eosinophilia: clinical and laboratory results on a U.S.kindred. Am J Med Genet. 1998;76:229-237.
  19. Yakulis R, Bedetti CD.  Loffler’s endocarditis: occurrence with malignant lymphoma with a high content of epithelioid histiocytes (‘Lennert’s lymphoma’). Arch Pathol Lab Med. 1983;107:531-534.
  20. Chusid MJ, Dale DC, West BC, Wolff SM.  The hypereosinophilic syndrome: analysis of fourteen cases with review of the literature. Medicine (Baltimore). 1975;54:1-27.
  21. Bakhshi S, Hamre M, Mohamed AN, Feldman G, Ravindranath Y.  t(5;9)(q11;q34): a novel familial translocation involving Abelson oncogene and association with hypereosinophilia. J Pediatr Hematol Oncol. 2003;25:82-84.
  22. Rioux JD, Stone VA, Daly MJ, et al. Familial eosinophilia maps to the cytokine gene cluster on human chromosomal region 5q31-q33. Am J Hum Genet. 1998;63:1086-1094.
  23. Baxter EJ, Kulkarni S, Vizmanos J-L, et al. Novel translocations that disrupt the platelet-derived growth factor receptor ß (PDGFRB) gene in BCR–ABL-negative chronic myeloproliferative disorders. Br J Haematol. 2003;120:251-256.
  24. Klion AD, Law MA, Riemenschneider W, et al. Familial eosinophilia: a benign disorder? Blood. 2004;103:4050-4055.
  25. Evengard B.  Diagnostic and clinical aspects of schistosomiasis in 182 patients treated at a Swedish ward for tropical diseases during a 10-year period. Scand J Infect Dis. 1990;22:585-594.
  26. Zinkham WH.  Visceral larva migrans: a review and reassessment indicating two forms of clinical expression: visceral and ocular. Am J Dis Child. 1978;132:627-633.
  27. Milder JE, Walzer PD, Kilgore G, Rutherford I, Klein M.  Clinical features of Strongyloides stercoralis infection in an endemic area of the United States. Gastroenterology. 1981;80:1481-1488.
  28. Hussain R, Hamilton RG, Kumaraswami V, Adkinson NFJr, Ottesen EA.  IgE responses in human filariasis, I: quantitation of filaria-specific IgE. J Immunol. 1981;127:1623-1629.
  29. Maxwell C, Hussain R, Nutman TB, et al. The clinical and immunologic responses of normal human volunteers to low dose hookworm (Necator americanus) infection. Am J Trop Med Hyg. 1987;37:126-134.
  30. Arjona R, Riancho JA, Aguado JM, Salesa R, Gonzalez-Macias J.  Fascioliasis in developed countries: a review of classic and aberrant forms of the disease. Medicine (Baltimore). 1995;74:13-23.
  31. Pozio E, Varese P, Morales MA, Croppo GP, Pelliccia D, Bruschi F.  Comparison of human trichinellosis caused by Trichinella spiralis and by Trichinella britovi. Am J Trop Med Hyg. 1993;48:568-575.
  32. Uchiyama F, Morimoto Y, Nawa Y.  Re-emergence of paragonimiasis in Kyushu, Japan. Southeast Asian J Trop Med Public Health. 1999;30:686-691.
  33. Windsor JJ, Johnson EH.  Dientamoeba fragilis: the unflagellated human flagellate. Br J Biomed Sci. 1999;56:293-306.
  34. Grant SC, Klein C.  Toxoplasma gondii encephalitis in an immunocompetent adult: a case report. S Afr Med J. 1987;71:585-587.
  35. Junod C.  Isospora belli coccidiosis in immunocompetent subjects (a study of 40 cases seen in Paris) [in French]. Bull Soc Pathol Exot Filiales. 1988;81:317-325.
  36. Granter SR, Barnhill RL, Duray PH.  Borrelial fasciitis: diffuse fasciitis and peripheral eosinophilia associated with Borrelia infection. Am J Dermatopathol. 1996;18:465-473.
  37. Tietz A, Sponagel L, Erb P, Bucher H, Battegay M, Zimmerli W.  Eosinophilia in patients infected with the human immunodeficiency virus. Eur J Clin Microbiol Infect Dis. 1997;16:675-677.
  38. Spry CJ.  Eosinophilia and allergic reactions to drugs. Clin Haematol. 1980;9:521-534.
  39. Tas S, Simonart T.  Management of drug rash with eosinophilia and systemic symptoms (DRESS syndrome): an update. Dermatology. 2003;206:353-356.
  40. Ichiche M, Kiesch N, De Bels D.  DRESS syndrome associated with HHV-6 reactivation. Eur J Intern Med. 2003;14:498-500.
  41. De Marco P, Melchiori G.  Carbamazepine and eosinophilia [letter]. Ann Neurol. 1986;20:274.
  42. Gonzales-Chambers R, Rosenfeld C, Winkelstein A, Dameshek L.  Eosinophilia resulting from administration of recombinant granulocyte-macrophage colony-stimulating factor (rhGM-CSF) in a patient with T-gamma lymphoproliferative disease. Am J Hematol. 1991;36:157-159.
  43. Seebach J, Speich R, Fehr J, Tuchschmid P, Russi E.  GM-CSF-induced acute eosinophilic pneumonia. Br J Haematol. 1995;90:963-965.
  44. Trojan A, Meier R, Licht A, Taverna C.  Eosinophilic pneumonia after administration of fludarabine for the treatment of non-Hodgkin’s lymphoma. Ann Hematol. 2002;81:535-537.
  45. Yamakado S, Yoshida Y, Yamada T, Kishida T, Kobayashi M, Nomura T.  Pulmonary infiltration and eosinophilia associated with sulfasalazine therapy for ulcerative colitis: a case report and review of literature. Intern Med. 1992;31:108-113.
  46. Clauw DJ, Nashel DJ, Umhau A, Katz P.  Tryptophan-associated eosinophilic connective-tissue disease: a new clinical entity? JAMA. 1990;263:1502-1506.
  47. Kilbourne EM, Posada de la Paz M, Abaitua Borda I, Diez Ruiz-Navarro M, Philen RM, Falk H.  Toxic oil syndrome: a current clinical and epidemiologic summary, including comparisons with the eosinophilia-myalgia syndrome. J Am Coll Cardiol. 1991;18:711-717.
  48. Mert A, Tabak F, Aktuglu Y.  Eosinophilia in toxic shock syndrome: review of 20 cases [letter]. Scand J Infect Dis. 1998;30:320.
  49. Griffin E, Hakansson L, Formgren H, Jorgensen K, Peterson C, Venge P.  Blood eosinophil number and activity in relation to lung function in patients with asthma and with eosinophilia. J Allergy Clin Immunol. 1991;87:548-557.
  50. Uehara M, Izukura R, Sawai T.  Blood eosinophilia in atopic dermatitis. Clin Exp Dermatol. 1990;15:264-266.
  51. Chapman BJ, Capewell S, Gibson R, Greening AP, Crompton GK.  Pulmonary eosinophilia with and without allergic bronchopulmonary aspergillosis. Thorax. 1989;44:919-924.
  52. Desenne JJ, Acquatella G, Stern R, Muller A, Sanchez M, Somoza R.  Blood eosinophilia in Hodgkin’s disease: a follow-up of 25 cases in Venezuela. Cancer. 1992;69:1248-1253.
  53. Scales JW, McMichael A.  Persistent peripheral eosinophilia and cutaneous non-Hodgkin’s lymphoma: a case report and review of the literature. Cutis. 2001;67:67-70.
  54. Watanabe K, Shinbo T, Kojima M, Naito M, Tanahashi N, Nara M.  Bcell lymphoma associated with eosinophilia. Cancer. 1989;64:1682-1685.
  55. Navarro-Roman L, Medeiros LJ, Kingma DW, et al. Malignant lymphomas of B-cell lineage with marked tissue eosinophilia: a report of five cases. Am J Surg Pathol. 1994;18:347-356.
  56. Fridlender ZG, Simon HU, Shalit M.  Metastatic carcinoma presenting with concomitant eosinophilia and thromboembolism. Am J Med Sci. 2003;326:98-101.
  57. Walter R, Joller-Jemelka HI, Salomon F.  Metastatic squamous cell carcinoma with marked blood eosinophilia and elevated serum interleukin-5 levels [letter]. Exp Hematol. 2002;30:1-2.
  58. Spry C.  Eosinophilia in Addison’s disease. Yale J Biol Med. 1976;49:411-413.
  59. Garcia-Zepeda EA, Rothenberg ME, Ownbey RT, Celestin J, Leder P, Luster AD.  Human eotaxin is a specific chemoattractant for eosinophil cells and provides a new mechanism to explain tissue eosinophilia. Nat Med. 1996;2:449-456.
  60. Teruya-Feldstein J, Jaffe ES, Burd PR, Kingma DW, Setsuda JE, Tosato G.  Differential chemokine expression in tissues involved by Hodgkin’s disease: direct correlation of eotaxin expression and tissue eosinophilia. Blood. 1999;93:2463-2470.
  61. Balducci L, Chapman SW, Little DD, Hardy CL.  Paraneoplastic eosinophilia: report of a case with in vitro studies of hemopoiesis. Cancer. 1989;64:2250-2253.
  62. Sanada I, Asou N, Kojima S, Kawano F, Shido T, Takatsuki K.  Acute myelogenous leukemia (FAB M1) associated with t(5;16) and eosinophilia: report of an additional case. Cancer Genet Cytogenet. 1989;43:139-141.
  63. Blatt PM, Rothstein G, Miller HL, Cathey WJ.  Loffler’s endomyocardial fibrosis with eosinophilia in association with acute lymphoblastic leukemia. Blood. 1974;44:489-493.
  64. Keung YK, Beaty M, Steward W, Jackle B, Pettnati M.  Chronic myelocytic leukemia with eosinophilia, t(9;12)(q34;p13), and ETV6-ABL gene rearrangement: case report and review of the literature. Cancer Genet Cytogenet. 2002;138:139-142.
  65. Kuroda J, Kimura S, Akaogi T, et al. Myelodysplastic syndrome with clonal eosinophilia accompanied by eosinophilic pulmonary interstitial infiltration. Acta Haematol. 2000;104:119-123.
  66. Wilkinson K, Velloso ER, Lopes LF, et al. Cloning of the t(1;5)(q23;q33) in a myeloproliferative disorder associated with eosinophilia: involvement of PDGFRB and response to imatinib. Blood. 2003;102:4187-4190.
  67. Bain BJ.  Cytogenetic and molecular genetic aspects of eosinophilic leukaemias. Br J Haematol. 2003;122:173-179.
  68. Ma SK, Kwong YL, Shek TW, et al. The role of trisomy 8 in the pathogenesis of chronic eosinophilic leukemia. Hum Pathol. 1999;30:864-868.
  69. Yam LT, Yam CF, Li CY.  Eosinophilia in systemic mastocytosis. Am J Clin Pathol. 1980;73:48-54.
  70. Bennett JM, Catovsky D, Daniel MT, et al. The chronic myeloid leukaemias: guidelines for distinguishing chronic granulocytic, atypical chronic myeloid, and chronic myelomonocytic leukaemia: proposals by the French-American-British Cooperative Leukaemia Group. Br J Haematol. 1994;87:746-754.
  71. Heldin CH, Westermark B.  Mechanism of action and in vivo role of platelet-derived growth factor. Physiol Rev. 1999;79:1283-1316.
  72. Pardanani A, Brockman SR, Paternoster SF, et al. FIP1L1-PDGFRA fusion: prevalence and clinicopathologic correlates in 89 consecutive patients with moderate to severe eosinophilia. Blood. 2004;104:3038-3045.
  73. Elliott MA, Pardanani A, Li CY, Tefferi A.  Immunophenotypic normalization of aberrant mast cells accompanies histological remission in imatinibtreated patients with eosinophilia-associated mastocytosis [letter]. Leukemia. 2004;18:1027-1029.
  74. Pardanani A, Ketterling RP, Brockman SR, et al. CHIC2 deletion, a surrogate for FIP1L1-PDGFRA fusion, occurs in systemic mastocytosis associated with eosinophilia and predicts response to imatinib mesylate therapy. Blood. 2003;102:3093-3096.
  75. Cools J, DeAngelo DJ, Gotlib J, et al. A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. N Engl J Med. 2003;348:1201-1214.
  76. Baxter EJ, Hochhaus A, Bolufer P, et al. The t(4;22)(q12;q11) in atypical chronic myeloid leukaemia fuses BCR to PDGFRA. Hum Mol Genet. 2002;11:1391-1397.
  77. Miranda RN, Esparza AR, Sambandam S, Medeiros LJ.  Systemic mast cell disease presenting with peripheral blood eosinophilia. Hum Pathol. 1994;25:727-730.
  78. Klion AD, Robyn J, Akin C, et al. Molecular remission and reversal of myelofibrosis in response to imatinib mesylate treatment in patients with the myeloproliferative variant of hypereosinophilic syndrome. Blood. 2004;103:473-478.
  79. Vandenberghe P, Wlodarska I, Michaux L, et al. Clinical and molecular features of FIP1L1-PDFGRA (+) chronic eosinophilic leukemias. Leukemia. 2004;18:734-742.
  80. Golub TR, Barker GF, Lovett M, Gilliland DG.  Fusion of PDGF receptor beta to a novel ets-like gene, tel, in chronic myelomonocytic leukemia with t(5;12) chromosomal translocation. Cell. 1994;77:307-316.
  81. Granjo E, Lima M, Lopes JM, et al. Chronic eosinophilic leukaemia presenting with erythroderma, mild eosinophilia and hyper-IgE: clinical, immunological and cytogenetic features and therapeutic approach: a case report. Acta Haematol. 2002;107:108-112.
  82. Apperley JF, Gardembas M, Melo JV, et al. Response to imatinib mesylate in patients with chronic myeloproliferative diseases with rearrangements of the platelet-derived growth factor receptor beta. N Engl J Med. 2002;347:481-487.
  83. Gupta R, Knight CL, Bain BJ.  Receptor tyrosine kinase mutations in myeloid neoplasms. Br J Haematol. 2002;117:489-508.
  84. Macdonald D, Reiter A, Cross NC.  The 8p11 myeloproliferative syndrome: a distinct clinical entity caused by constitutive activation of FGFR1. Acta Haematol. 2002;107:101-107.
  85. Sohal J, Chase A, Mould S, et al. Identification of four new translocations involving FGFR1 in myeloid disorders. Genes Chromosomes Cancer. 2001;32:155-163.
  86. Fauci AS, Harley JB, Roberts WC, Ferrans VJ, Gralnick HR, Bjornson BH.  The idiopathic hypereosinophilic syndrome: clinical, pathophysiologic, and therapeutic considerations [NIH conference]. Ann Intern Med. 1982;97:78-92.
  87. Liesveld JL, Abboud CN.  State of the art: the hypereosinophilic syndromes. Blood Rev. 1991;5:29-37.
  88. Lin DA, Boyce JA.  The idiopathic hypereosinophilic syndrome. Allergy Asthma Proc. 2003;24:417-420.
  89. Owen J, Scott JG.  Transition of the hypereosinophilic syndrome to myelomonocytic leukemia. Can Med Assoc J. 1979;121:1489-1491.
  90. Yoo TJ, Orman SV, Patil SR, et al. Evolution to eosinophilic leukemia with a t(5:11) translocation in a patient with idiopathic hypereosinophilic syndrome. Cancer Genet Cytogenet. 1984;11:389-394.
  91. Needleman SW, Mane SM, Gutheil JC, Kapil V, Heyman MR, Testa JR.  Hypereosinophilic syndrome with evolution to myeloproliferative disorder: temporal relationship to loss of Y chromosome and c-N-ras activation. Hematol Pathol. 1990;4:149-155.
  92. Chang HW, Leong KH, Koh DR, Lee SH.  Clonality of isolated eosinophils in the hypereosinophilic syndrome. Blood. 1999;93:1651-1657.
  93. Roufosse F, Schandene L, Sibille C, et al. Clonal Th2 lymphocytes in patients with the idiopathic hypereosinophilic syndrome. Br J Haematol. 2000;109:540-548.
  94. Raghavachar A, Fleischer S, Frickhofen N, Heimpel H, Fleischer B.  T lymphocyte control of human eosinophilic granulopoiesis: clonal analysis in an idiopathic hypereosinophilic syndrome. J Immunol. 1987;139:3753-3758.
  95. Simon HU, Plotz SG, Dummer R, Blaser K.  Abnormal clones of T cells producing interleukin-5 in idiopathic eosinophilia. N Engl J Med. 1999;341:1112-1120.
  96. Spry CJ, Davies J, Tai PC, Olsen EG, Oakley CM, Goodwin JF.  Clinical features of fifteen patients with the hypereosinophilic syndrome. Q J Med. 1983;52:1-22.
  97. Kazmierowski JA, Chusid MJ, Parrillo JE, Fauci AS, Wolff SM.  Dermatologic manifestations of the hypereosinophilic syndrome. Arch Dermatol. 1978;114:531-535.
  98. Leiferman KM, O’Duffy JD, Perry HO, Greipp PR, Giuliani ER, Gleich GJ.  Recurrent incapacitating mucosal ulcerations: a prodrome of the hypereosinophilic syndrome. JAMA. 1982;247:1018-1020.
  99. Bogenrieder T, Griese DP, Schiffner R, et al. Wells’ syndrome associated with idiopathic hypereosinophilic syndrome. Br J Dermatol. 1997;137:978-982.
  100. Parrillo JE, Borer JS, Henry WL, Wolff SM, Fauci AS.  The cardiovascular manifestations of the hypereosinophilic syndrome: prospective study of 26 patients, with review of the literature. Am J Med. 1979;67:572-582.
  101. Sato Y, Taniguchi R, Yamada T, et al. Measurement of serum concentrations of cardiac troponin T in patients with hypereosinophilic syndrome: a sensitive non-invasive marker of cardiac disorder [letter]. Intern Med. 2000;39:350.
  102. Dorfman LJ, Ransom BR, Forno LS, Kelts A.  Neuropathy in the hypereosinophilic syndrome. Muscle Nerve. 1983;6:291-298.
  103. Moore PM, Harley JB, Fauci AS.  Neurologic dysfunction in the idiopathic hypereosinophilic syndrome. Ann Intern Med. 1985;102:109-114.
  104. Weingarten JS, O’Sheal SF, Margolis WS.  Eosinophilic meningitis and the hypereosinophilic syndrome: case report and review of the literature. Am J Med. 1985;78:674-676.
  105. Tsai CP, Yeh HH, Tsai JJ, Lin KP, Wu ZA.  Transverse myelitis and polyneuropathy in idiopathic hypereosinophilic syndrome [letter]. Muscle Nerve. 1993;16:112-113.
  106. Slabbynck H, Impens N, Naegels S, Dewaele M, Schandevyl W.  Idiopathic hypereosinophilic syndrome-related pulmonary involvement diagnosed by bronchoalveolar lavage. Chest. 1992;101:1178-1180.
  107. Winn RE, Kollef MH, Meyer JI.  Pulmonary involvement in the hypereosinophilic syndrome. Chest. 1994;105:656-660.
  108. Kang EY, Shim JJ, Kim JS, Kim KI.  Pulmonary involvement of idiopathic hypereosinophilic syndrome: CT findings in five patients. J Comput Assist Tomogr. 1997;21:612-615.
  109. Scheurlen M, Mork H, Weber P.  Hypereosinophilic syndrome resembling chronic inflammatory bowel disease with primary sclerosing cholangitis. J Clin Gastroenterol. 1992;14:59-63.
  110. Catalano L, Pastena S, Catalano M, Lestini A, Valentini G, Rotoli B.  Eosinophilic gastroenteritis: a rare localization of the hypereosinophilic syndrome? [letter]. Haematologica. 1992;77:292-293.
  111. Grauer L, Padilla VMIII, Bouza L, Barkin JS.  Eosinophilic sclerosing cholangitis associated with hypereosinophilic syndrome. Am J Gastroenterol. 1993;88:1764-1769.
  112. Ichikawa N, Taniguchi A, Akama H, et al. Sclerosing cholangitis associated with hypereosinophilic syndrome. Intern Med. 1997;36:561-564.
  113. Elouaer-Blanc L, Zafrani ES, Farcet JP, Saint-Marc Girardin MF, Mathieu D, Dhumeaux D.  Hepatic vein obstruction in idiopathic hypereosinophilic syndrome. Arch Intern Med. 1985;145:751-753.
  114. Vargas CA, Maldonado O, Botero RC, et al. Budd-Chiari syndrome associated with the hypereosinophilic syndrome [letter]. Am J Gastroenterol. 1993;88:1802-1803.
  115. Chaine G, Davies J, Kohner EM, Hawarth S, Spry CJ.  Ophthalmologic abnormalities in the hypereosinophilic syndrome. Ophthalmology. 1982;89:1348-1356.
  116. Peison B, Benisch B, Lim M, Chin JC.  Idiopathic hypereosinophilic syndrome with polymyositis. South Med J. 1988;81:403-406.
  117. Bulucu F, Can C, Inal V, Baykal Y, Erikci S.  Renal involvement in a patient with idiopathic hypereosinophilic syndrome [letter]. Clin Nephrol. 2002;57:171-173.
  118. Prattichizzo FA, Bernini L.  An idiopathic hypereosinophilic syndrome mimicking seronegative rheumatoid arthritis: 20-year follow-up with clinical and laboratory findings. Clin Exp Rheumatol. 1992;10:79-81.
  119. Appelbaum FR.  Molecular diagnosis and clinical decisions in adult acute leukemia. Semin Hematol. 1999;36:401-410.
  120. O’Brien SG, Guilhot F, Larson RA, et al IRIS Investigators. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003;348:994-1004.
  121. Druker BJ, Tamura S, Buchdunger E, et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med. 1996;2:561-566.
  122. Buchdunger E, Zimmermann J, Mett H, et al. Inhibition of the Abl protein-tyrosine kinase in vitro and in vivo by a 2-phenylaminopyrimidine derivative. Cancer Res. 1996;56:100-104.
  123. Deininger MW, Goldman JM, Lydon N, Melo JV.  The tyrosine kinase inhibitor CGP57148B selectively inhibits the growth of BCR-ABL-positive cells. Blood. 1997;90:3691-3698.
  124. Carroll M, Ohno-Jones S, Tamura S, et al. CGP 57148, a tyrosine kinase inhibitor, inhibits the growth of cells expressing BCR-ABL, TEL-ABL, and TEL-PDGFR fusion proteins. Blood. 1997;90:4947-4952.
  125. Heinrich MC, Griffith DJ, Druker BJ, Wait CL, Ott KA, Zigler AJ.  Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor. Blood. 2000;96:925-932.
  126. Schindler T, Bornmann W, Pellicena P, Miller WT, Clarkson B, Kuriyan J.  Structural mechanism for STI-571 inhibition of abelson tyrosine kinase. Science. 2000;289:1938-1942.
  127. Tefferi A, Pardanani A.  Clinical, genetic, and therapeutic insights into systemic mast cell disease. Curr Opin Hematol. 2004;11:58-64.
  128. Takeuchi K, Koike K, Kamijo T, et al. STI571 inhibits growth and adhesion of human mast cells in culture. J Leukoc Biol. 2003;74:1026-1034.
  129. Akin C, Brockow K, D’Ambrosio C, et al. Effects of tyrosine kinase inhibitor STI571 on human mast cells bearing wild-type or mutated c-kit. Exp Hematol. 2003;31:686-692.
  130. Zermati Y, De Sepulveda P, Feger F, et al. Effect of tyrosine kinase inhibitor STI571 on the kinase activity of wild-type and various mutated c-kit receptors found in mast cell neoplasms. Oncogene. 2003;22:660-664.
  131. Pardanani A, Elliott M, Reeder T, et al. Imatinib for systemic mast-cell disease. Lancet. 2003;362:535-536.
  132. Dispenzieri A, Kyle RA, Lacy MQ, et al. Superior survival in primary systemic amyloidosis patients undergoing peripheral blood stem cell transplantation: a case-control study. Blood. 2004;103:3960-3963.
  133. Martinelli G, Malagola M, Ottaviani E, Rosti G, Trabacchi E, Baccarani M.  Imatinib mesylate can induce complete molecular remission in FIP1L1-PDGFR-a positive idiopathic hypereosinophilic syndrome [letter]. Haematologica. 2004;89:236-237.
  134. Frickhofen N, Marker-Hermann E, Reiter A, et al. Complete molecular remission of chronic eosinophilic leukemia complicated by CNS disease after targeted therapy with imatinib. Ann Hematol. 2004;83:477-480.
  135. Rose C, Dupire S, Roche-Lestienne C, et al. Sustained molecular response with imatinib in a leukemic form of idiopathic hypereosinophilic syndrome in relapse after allograft [letter]. Leukemia. 2004;18:354-355.
  136. Pitini V, Arrigo C, Teti D, Barresi G, Righi M, Alo G.  Response to STI571 in chronic myelomonocytic leukemia with platelet derived growth factor beta receptor involvement: a new case report. Haematologica. 2003;88:ECR18.
  137. Parrillo JE, Fauci AS, Wolff SM.  Therapy of the hypereosinophilic syndrome. Ann Intern Med. 1978;89:167-172.
  138. Schooley RT, Flaum MA, Gralnick HR, Fauci AS.  A clinicopathologic correlation of the idiopathic hypereosinophilic syndrome, II: clinical manifestations. Blood. 1981;58:1021-1026.
  139. Zabel P, Schlaak M.  Cyclosporin for hypereosinophilic syndrome. Ann Hematol. 1991;62:230-231.
  140. Sakamoto K, Erdreich-Epstein A, deClerck Y, Coates T.  Prolonged clinical response to vincristine treatment in two patients with idiopathic hypereosinophilic syndrome. Am J Pediatr Hematol Oncol. 1992;14:348-351.
  141. Marshall GM, White L.  Effective therapy for a severe case of the idiopathic hypereosinophilic syndrome. Am J Pediatr Hematol Oncol. 1989;11:178-183.
  142. Fruehauf S, Fiehn C, Haas R, Doehner H, Hunstein W.  Sustained remission of idiopathic hypereosinophilic syndrome following alpha-interferon therapy. Acta Haematol. 1993;89:91-93.
  143. Butterfield JH, Gleich GJ.  Response of six patients with idiopathic hypereosinophilic syndrome to interferon alfa. J Allergy Clin Immunol. 1994;94(6, pt 2):1318-1326.
  144. Ceretelli S, Capochiani E, Petrini M.  Interferon-a in the idiopathic hypereosinophilic syndrome: consideration of five cases. Ann Hematol. 1998;77:161-164.
  145. Ueno NT, Zhao S, Robertson LE, Consoli U, Andreeff M.  2-Chlorodeoxyadenosine therapy for idiopathic hypereosinophilic syndrome [letter]. Leukemia. 1997;11:1386-1390.
  146. Smit AJ, van Essen LH, de Vries EG.  Successful long-term control of idiopathic hypereosinophilic syndrome with etoposide. Cancer. 1991;67:2826-2827.
  147. Sigmund DA, Flessa HC.  Hypereosinophilic syndrome: successful allogeneic bone marrow transplantation. Bone Marrow Transplant. 1995;15:647-648.
  148. Fukushima T, Kuriyama K, Ito H, et al. Successful bone marrow transplantation for idiopathic hypereosinophilic syndrome. Br J Haematol. 1995;90:213-215.
  149. Juvonen E, Volin L, Koponen A, Ruutu T.  Allogeneic blood stem cell transplantation following non-myeloablative conditioning for hypereosinophilic syndrome. Bone Marrow Transplant. 2002;29:457-458.
  150. Ueno NT, Anagnostopoulos A, Rondon G, et al. Successful non-myeloablative allogeneic transplantation for treatment of idiopathic hypereosinophilic syndrome. Br J Haematol. 2002;119:131-134.
  151. Klion AD, Law MA, Noel P, Kim YJ, Haverty TP, Nutman TB.  Safety and efficacy of the monoclonal anti-interleukin-5 antibody SCH55700 in the treatment of patients with hypereosinophilic syndrome. Blood. 2004;103:2939-2941.
  152. Garrett JK, Jameson SC, Thomson B, et al. Anti-interleukin-5 (mepolizumab) therapy for hypereosinophilic syndromes. J Allergy Clin Immunol. 2004;113:115-119.
  153. Plotz SG, Simon HU, Darsow U, et al. Use of an anti-interleukin-5 antibody in the hypereosinophilic syndrome with eosinophilic dermatitis. N Engl J Med. 2003;349:2334-2339.
  154. Sefcick A, Sowter D, DasGupta E, Russell NH, Byrne JL.  Alemtuzumab therapy for refractory idiopathic hypereosinophilic syndrome [letter]. Br J Haematol. 2004;124:558-559.
  155. Koury MJ, Newman JH, Murray JJ.  Reversal of hypereosinophilic syndrome and lymphomatoid papulosis with mepolizumab and imatinib [letter]. Am J Med. 2003;115:587-589.
  156. Pardanani A, Reeder T, Porrata LF, et al. Imatinib therapy for hypereosinophilic syndrome and other eosinophilic disorders. Blood. 2003;101:3391-3397.
  157. Pitini V, Arrigo C, Azzarello D, et al. Serum concentration of cardiac Troponin T in patients with hypereosinophilic syndrome treated with imatinib is predictive of adverse outcomes [letter]. Blood. 2003;102:3456-3457.
  158. Gleich GJ, Leiferman KM, Pardanani A, Tefferi A, Butterfield JH.  Treatment of hypereosinophilic syndrome with imatinib mesilate. Lancet. 2002;359:1577-1578.
  159. Shah NP, Tran C, Lee FY, Chen P, Norris D, Sawyers CL.  Overriding imatinib resistance with a novel ABL kinase inhibitor. Science. 2004;305:399-401.
  160. Tipping AJ, Baluch S, Barnes DJ, et al. Efficacy of dual-specific Bcr-Abl and Src-family kinase inhibitors in cells sensitive and resistant to imatinib mesylate. Leukemia. 2004;18:1352-1356.
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