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Three cases of feline hypereosinophilic syndrome treated with imatinib mesilate
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CLINICAL CASE
Three cases of feline hypereosinophilic syndrome treated with imatinib mesilate夽 Trois cas de syndrome hyperéosinophilique félin traités avec de l’imatinib mésylate N. Cochet Faivre a,∗,b,c, P. Prelaud a, E. Bensignor d,e,f, J. Declercq g, V. Defalque h a
Advetia, 5, rue Dubrunfaut, 75012 Paris, France Clinique vétérinaire des Halles, 28, Faubourd de Saverne, 67000 Strasbourg, France c Parasitology mycology dermatology-ENVA, 7, avenue Gal-de-Gaulle, 94704 Maisons-Alfort, France d Clinique vétérinaire, 6, rue Mare-Pavée, 35510 Rennes-Cesson, France e Clinique vétérinaire, 17, boulevard des Filles-du-Calvaire, 75003 Paris, France f Centre hospitalier vétérinaire, 22, rue Viviani, 44000 Nantes, France g Ghent university Salisburylaan, 133 9820 Merelbeke, Belgium h Department of clinical studies, Ontario veterinary college, university of Guelph, Guelph, Ontario, Canada b
Received 5 January 2014; accepted 23 October 2014
KEYWORDS Cat; Hypereosinophilic syndrome; Eosinophilic dermatitis; Imatinib mesylate; Tyrosine-kinase inhibitor
Summary A hypereosinophilic syndrome was diagnosed in three cats with refractory dermatitis and marked hypereosinophilia. The cats were treated with imatinib mesylate, a tyrosine-kinase inhibitor at the oral dose of 5 mg per cat. In all three cases, a dramatic improvement was rapidly observed. © 2014 Published by Elsevier Masson SAS on behalf of AFVAC.
夽 Crédits de formation continue. — La lecture de cet article ouvre droit à 0,05 CFC. La déclaration de lecture, individuelle et volontaire, est à effectuer auprès du CNVFCC (cf. sommaire). ∗ Corresponding author. E-mail address: [email protected] (N. Cochet Faivre).
http://dx.doi.org/10.1016/j.anicom.2014.10.003 2214-5672/© 2014 Published by Elsevier Masson SAS on behalf of AFVAC.
Please cite this article in press as: Cochet Faivre N, et al. Three cases of feline hypereosinophilic syndrome treated with imatinib mesilate. Revue vétérinaire clinique (2014), http://dx.doi.org/10.1016/j.anicom.2014.10.003
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MOTS CLÉS Chat ; Syndrome hyperéosinophilique ; Dermatite éosinophilique ; Imatinib mesilate ; inhibiteur des tyrosine-kinases
Résumé Un syndrome hyperéosinophilique est diagnostiqué chez 3 chats présentant une dermatite éosinophilique réfractaire à tout traitement et une hyperéosinophilie marquée. Les chats sont traités avec de l’imatinib dosée à 5 mg. Dans les trois cas, une amélioration spectaculaire est observée. © 2014 Publié par Elsevier Masson SAS pour l’AFVAC.
Introduction Imatinib is an oral chemotherapeutic agent that selectively inhibits the protein tyrosine-kinases Bcr-Abl, Kit and PDGFR (platelet-derived growth factor receptor) involved in oncogenesis. It has demonstrated remarkable clinical efficacy in human patients with chronic myeloid leukemia, malignant gastrointestinal stromal tumours, chronic eosinophilic leukemia and the hypereosinophilic syndrome (HES) [1,2]. It is currently marketed in several countries worldwide as its mesylate salt, imatinib mesylate (Gleevec or Glivec, Novartis, Switzerland). In veterinary medicine, imatinib is currently not registered for the treatment of animal diseases. It has however been used off-label for the treatment of canine and feline mast cell tumors as well as feline fibrosarcoma and squamous cell carcinoma [3,4]. The authors report here three cases of feline hypereosinophilic syndrome dramatically improved with imatinib mesylate. To our knowledge, the use of this drug for the treatment of feline HES has never been previously reported.
Case reports Case 1 A 6-year-old neutered male domestic shorthaired cat was referred to severe pruritic eosinophilic dermatitis of more than 5-year duration associated, since 2 months, with, inspire of treatment with steroids, worsening cutaneous and oral lesions, ptyalism, painful food prehension, weight loss and lethargy. The initial lesions were a linear granuloma located on the pelvic limbs and an eosinophilic plaque located on the inner thigh. A limited antigen diet trial (DR21 Royal Canin), flea control (fipronil + (S)-methoprene spot on, every month), antibiotic therapy (cefalexin, 20 mg/kg/BID), oral ciclosporin (7 mg/kg/day) and oral chlorambucil (2 mg/kg every three days) were of no benefit. Oral and injectable glucocorticosteroid therapy (prednisolone at 2 mg/kg/day, dexamethasone at 0.2 mg/kg/day, methylprednisolone acetate at 20 mg/month) had only led to a partial improvement during a few years. But two months prior to presentation, a severe deterioration was observed in spite of an injection of 20 mg methylprednisolone acetate and a prescription of dexamethasone at 0.2 mg/kg/day. On physical examination at the time of referral, the cat had lost over than 1 kg, (weight 4 kg) and was lethargic.
Figure 1. Clinical case 1: very large budding eroded oozing plaque on the right elbow.
The submandibular, retropharyngeal and prescapular lymph nodes were enlarged. Several cutaneous lesions were noted: a very large eroded oozing plaque with a central fistula located on the right elbow (Fig. 1), an eroded plaque on the left thoracic limb and an ulcer on the upper lips. The hard palate was painful, erythematous, eroded and punctuated by numerous white granulomas (Fig. 2). The other physical parameters were within normal limits. A complete blood count revealed an increased eosinophil count (4.77 × 109 /L, reference range 0.05—1.10 × 109 /L). On peripheral blood smear, mature eosinophilia was noted. The serum biochemical parameters were within normal limits. Serological and polymerase chain reaction tests were negative for feline leukaemia virus (FeLV), feline immunodeficiency virus (FIV), feline herpesvirus type 1 (FHV1) and calicivirus. Faecal floating examination was negative for intestinal parasites. Cytological examination of all mucosal and cutaneous lesions revealed the eosinophilic nature of the inflammation. Histopathological examination of the skin over the elbow revealed necrosis of the epidermis substituted by a necrotic coagulum, fragmented collagen fibers, eosinophilic dusting, picnotic cells (eosinophils?), the epidermic base is neovascularized and interspersed with inflammatory cells (mainly eosinophilic). Based on the findings, HES was diagnosed. Treatment was initiated with oral imatinib mesylate at a dose of 1.25 mg/kg
Please cite this article in press as: Cochet Faivre N, et al. Three cases of feline hypereosinophilic syndrome treated with imatinib mesilate. Revue vétérinaire clinique (2014), http://dx.doi.org/10.1016/j.anicom.2014.10.003
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Three cases of feline hypereosinophilic syndrome treated with imatinib mesilate
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glucocorticosteroid therapy was prescribed (methylprednisolone at 4 mg EOD). After 51 weeks, the owner reported a relapse in the cutaneous lesions and the lethargy. A complete blood count revealed hypereosinophilia (3.74 × 109 /L). Combination therapy was reintroduced and consisted of imatinib mesylate administered at a dose of 5 mg/day and methylprednisolone at a dose of 2 mg/day. After 59 weeks, a complete blood count revealed no abnormality. Cutaneous lesions had dramatically improved. The frequency of administration of both drugs was therefore decreased (imatinib mesylate 5 mg EOD and methylprednisolone 2 mg EOD). After 5 years of EOD imatinib mesylate — methylprednisolone combination therapy (imatinib mesylate 5 mg EOD and methylprednisolone 1 mg EOD), the cat is still alive. Peripheral hypereosinophilia and cutaneous lesions are controlled.
Case 2
Figure 2. Clinical case 1: erythematous, eroded hard palate punctuated by numerous eosinophilic granulomas.
Figure 3. Clinical case 1: cicatriz on the right elbow 16 weeks after initiating treatment with imatinib mesylate.
of body weight (i.e. 5 mg/day). Lesion improvement was noticeable after 4 weeks of treatment and a 90%-regression of all lesions was observed after 16 weeks (Fig. 3). Thanks to the regression of oral lesions, the patient gained over 1 kg. Peripheral blood eosinophilia returned to normal values after 10 weeks of treatment. After 17 weeks, imatinib mesylate was prescribed at a dose of 5 mg every other day (EOD). After 27 weeks, however, while the eosinophil count was within normal limits (0.2 × 109 /L), cutaneous lesions were again observed on both thoracic limbs as well as the upper lips. Combination therapy was started and consisted of orally administered dexamethasone at a dose of 0.2 mg/kg/day and imatinib mesylate, a dose of 5 mg EOD. Two weeks later, cutaneous lesions were controlled and imatinib mesylate was withdrawn. Maintenance
An 8-year-old neutered male strictly indoor domestic shorthaired was referred to a history of several months of pruritus, weight loss, partial anorexia and soft stools. Cutaneous lesions started on the head and had progressed to involve the neck, trunk and limbs. A limited antigen diet trial was unhelpful. Oral prednisolone (1 mg/kg/day) led to minor improvement. Histopathological examination of skin biopsies revealed a hyperplastic spongiotic eosinophilic dermatitis. On physical examination at the time of referral, the cat was very thin and weighed 2.4 kg. Skin lesions consisted of alopecia, erythematous erosions and crusts on the head, neck, dorsum and thoracic limbs (Fig. 4a,b). Abdominal palpation revealed thickened bowel loops. Multiple coat brushing and skin scraping were negative for ectoparasites. Cytological examination from skin lesions direct impression smears revealed eosinophilic inflammation. Complete blood count revealed leukocytosis (54.6 × 109 /L, reference range 5.5—15.5 × 109 /L) related to hypereosinophilia (10.9 × 109 /L). Eosinophils, on blood smear cytological examination, were mature and of normal morphology. The serum biochemical parameters were within normal limits. Abdominal ultrasonography confirmed the increased thickness of intestinal walls. Cytological examination of ultrasound-guided fine needle aspiration of the intestines revealed the presence of eosinophils. Based on these findings, HES was diagnosed and treatment with imatinib mesylate was initiated at 5 mg/day orally. Within 4 weeks, the skin lesions started to regress and the cat’s appetite improved. At two months, there was marked improvement of lesions. Unfortunately, a few weeks later, the patient was found dead, most likely after a hit by car accident.
Case 3 A 20-month-old neutered male domestic shorthaired cat was referred to a 14-month history of pruritus and dermatitis. The cutaneous lesions started on the face and had progressively generalized. Vomiting and lethargy were also noted.
Please cite this article in press as: Cochet Faivre N, et al. Three cases of feline hypereosinophilic syndrome treated with imatinib mesilate. Revue vétérinaire clinique (2014), http://dx.doi.org/10.1016/j.anicom.2014.10.003
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Figure 5. Clinical case 3: multifocal to coalescing erythematous, eroded, crusty papules and extended alopecia on the back.
Figure 4. Clinical case 2: alopecia, erythematous erosions and crusts on the face (a) and lateral view of the cat with localization of cutaneous lesions (b).
ultrasonography showed moderate hepatosplenomegaly and thickening of the intestinal walls. Tests for FeLV and FIV were negative. Based on these findings, HES was diagnosed. Treatment consisted of imatinib mesylate at a dose of 5 mg/day, orally. The cat was rechecked one and two months after the initiation of the treatment. At the first recheck, the condition of the cat had improved considerably, evidenced by the decrease in the pruritus and the size of the cutaneous lesions. At the next follow-up appointment, the pruritus had continued to decrease and all cutaneous lesions had resolved. Due to the cost of imatinib mesylate tablets, the owner declined further treatment and the cat was unfortunately lost to follow-up.
Discussion A limited antigen diet trial (DR21 Royal Canin), flea control (fipronil + (S)-methoprene spot on, every month),and antibiotic therapy (cefalexin 25 mg/kg BID) were inefficient. There was an initial improvement with orally administered dexamethasone 0.1 mg/kg/day but this medication lost its efficacy over time. Ciclosporin was then introduced orally (25 mg/day) with improvement after 30 days, however the disease worsened when the dose was tapered. On physical examination at the time of referral, the cat was thin (3 kg) and weak. Submandibular and popliteal lymph nodes were enlarged. Cutaneous lesions were predominantly located on the face, the dorsum and the abdomen. The cat had multifocal to coalescing erythematous, eroded, crusty papules and extensive alopecia (Fig. 5). Crusts and ulcers were noted on the margin of the pinnae. Focal, raised, erythematous, crusty eroded plaques were observed on the neck and the face. Two complete blood counts performed at a 2-week interval revealed hypereosinophilia ranging from 2.7 × 109 /L to 3.7 × 109 /L. On peripheral blood smear cytological examination, mature eosinophilia was noted. The serum biochemical parameters were within normal limits. Multiple skin scrapings were negative. Cytological examination from direct impression smears of skin lesions showed eosinophilic inflammation. Histopathological examination of skin biopsies revealed a superficial and deep, interstitial to perivascular, predominantly eosinophilic inflammation. Abdominal
In humans, the hypereosinophilic syndrome (HES) is defined as a heterogeneous group of rare diseases characterized by the presence of marked peripheral blood eosinophilia (greater than 1.5 × 109 /L), the absence of a secondary cause for the eosinophilia, and evidence of eosinophil-associated organ damage [5,6]. Recent techniques have allowed the characterization of human HES subtypes by their precise immunologic and genetic abnormalities. The two best described subtypes are the lymphocytic variant HES (L-HES), in which the underlying cause for the eosinophilia is the secretion of eosinophilopoietic cytokines by T lymphocytes, and myeloproliferative HES/chronic eosinophilic leukemia (CEL), most commonly caused by an interstitial deletion in chromosome 4 [2,7,8]. This deletion results in the creation of the Fip1like1-platelet-derived growth factor receptor-alpha gene fusion mutation (FIP1L1-PDGFR˛ or F/P +). This fusion gene encodes for a constitutively active tyrosine kinase, which was found to be responsible for the eosinophilia. These subtypes are associated with differences in clinical presentation, prognosis and responses to therapy. For example, although recognized as the more aggressive form of HES, F/P+ has become of much better prognosis thanks to the use of tyrosine kinase inhibitors [9]. The lymphocytic variant is, on the other hand, non-responsive to imatinib mesylate treatment [10].
Please cite this article in press as: Cochet Faivre N, et al. Three cases of feline hypereosinophilic syndrome treated with imatinib mesilate. Revue vétérinaire clinique (2014), http://dx.doi.org/10.1016/j.anicom.2014.10.003
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Three cases of feline hypereosinophilic syndrome treated with imatinib mesilate In the feline species, HES is defined as a rare disease of unknown aetiology that occurs primarily and is also characterized by persistent peripheral blood eosinophilia and organ infiltration by eosinophils that eventually cause organ failure [11]. Human HES tends to occur in patients aged from 20 to 50 years of age, although all age groups may be affected. A recent retrospective study reports a male/female ratio of 11/8 [10]. The F/P+ disease variant affects almost exclusively male patients. The age of affected cats ranges from 10 months to 12 years of age. A female predisposition has been observed in one study [12]. As described in humans, all cats reported in this study were males but our sample of three cats is too small to be representative. The organs most frequently involved in humans suffering from HES include the skin, the lungs, the heart, the nervous system and gastrointestinal tract, although virtually any tissue or organ can be infiltrated by eosinophils [2,6,10,13]. Dermatologic manifestations are non-specific and consist either in pruritus, urticaria, angioedema, erythroderma or in erythematous nodules or papules evocating eczema. Patients with L-HES often have a history of atopic disease and almost all of them present with cutaneous manifestations. Mucosal lesions can be observed. Gastrointestinal symptoms may include abdominal pain, diarrhea, nausea and vomiting. Non-specific symptoms including weakness, fatigue, anorexia, fever and weight loss are common. In cats, the most frequently involved organs are the gastrointestinal tract, the spleen and mesenteric lymph nodes [14,15]. Furthermore, the eosinophilic infiltration can also target the skin, the bone marrow, the liver, the lung, the heart or the pancreas [16]. The dermatologic lesions in the cases described here were non-specific and all three cats had different dermatological lesions and lesion distribution. One cat (case number 2) had concurrent gastrointestinal symptoms and cutaneous signs. Another patient had mucosal and cutaneous lesions and a history of pruritic dermatitis lasting for more than 5 years (case number 1). The HES is a diagnosis of exclusion, after clonal eosinophilia (evidenced by the presence of histologic, cytogenetic, or molecular clue of an underlying myeloid malignancy) and reactive eosinophilia (due to diseases such as parasitic or viral infections, drugs, allergic and autoimmune diseases, neoplasia, etc.) have been rigorously ruled out [2]. To date, routine investigations supporting the diagnosis of HES in cats are limited to history, clinical presentation, complete blood count and the exclusion of other recognizable causes for the eosinophilia [17]. Medical imaging is used to detect the involvement of internal organs. Histopathological examination of tissue samples are useful to confirm the eosinophilic nature of tissue infiltration. A myelogram is not necessary to establish the diagnosis of HES but is helpful when suspecting a myeloproliferative disorder. If left untreated, HES is progressively fatal. Glucocorticosteroids remain the mainstay of treatment for most human patients. Alternative therapies for patients failing or not tolerating glucocorticosteroid therapy include cytotoxic agents (such as hydroxyurea and vincristine) and immunomodulatory agents (including ciclosporin), of which interferon-␣ showed the most promise. Recent diagnostic advances and the development of novel targeted therapies, including the
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tyrosine kinase inhibitors and humanized monoclonal antibodies, have expanded the armamentarium [1,2,10]. The successful empiric treatment with imatinib mesylate in a human patient with HES refractory to traditional therapy was first reported in 2001. This patient achieved a rapid and complete haematologic remission rapidly after imatinib mesylate treatment initiation. Imatinib mesylate is currently the first line of treatment for patient with HES induced by F/P rearrangement [10]. So far, no successful therapy has been described in feline HES except in one case that was controlled with prednisolone and hydroxyurea for more than 28 months [18]. We elected for the empirical use of imatinib mesylate in the three cases reported here for several reasons. First, most cases of feline HES reported in the literature had a poor prognosis with a rapidly fatal disease course, despite all attempts of treatment. The mean survival expectation from time of diagnosis to death is of only 7.5 weeks [14]. Secondly, their disease was refractory to initial treatments with glucocorticosteroids, chlorambucil or ciclosporin. Third, the response to imatinib mesylate reported in certain human HES subtypes seemed promising to the authors. Furthermore, there is anecdotal evidence that imatinib mesylate is very well tolerated in cats. In one study, no signs of toxicity, as evaluated by complete blood count and serum biochemistry, were noted in 8 of the 9 tumor-bearing cats treated with imatinib mesylate, and minimal gastrointestinal toxicity (vomiting) was observed in one cat only [4]. Lastly, we obtained informed consent from the owners. At the time we treated our three patients with imatinib, both masitinib and toracenib were not commercially available and approved for use in veterinary medicine. In our patients, the daily dose of imatinib mesylate was 5 mg, varying from 1.25 to 2 mg/kg. In view of the absence of evidence-based recommendations in the veterinary literature outlining the efficient dose of oral imatinib mesylate in the feline species, this dose was chosen arbitrarily. Human studies have shown that the average oral imatinib dose is between 100 mg and 400 mg per patient or 1.25—5.7 mg/kg (based on a body weight of 70 kg) [19]. Long-term tolerance was excellent in the case number 1; no haematological or biochemical abnormalities were observed after five years of treatment. In cases number 2 and 3, short-term tolerance was satisfying, but long-term follow-up was not feasible. As previously described in humans, treatment discontinuation was followed two months later by recurrence of the disease in case number 1 [2,20]. The disease rapidly improved within two months of treatment renewal. In this patient, the persistence of cutaneous lesions prompted the reintroduction of oral methylprednisolone in combination with imatinib mesylate in order to control clinical lesions. Such combination therapy is described in the human literature [13].
Conclusion The amazing improvement with imatinib mesylate in these patients and its excellent tolerance after five years of empirical treatment in one of them suggest that this drug is useful in the treatment of feline hypereosinophilic syndrome and
Please cite this article in press as: Cochet Faivre N, et al. Three cases of feline hypereosinophilic syndrome treated with imatinib mesilate. Revue vétérinaire clinique (2014), http://dx.doi.org/10.1016/j.anicom.2014.10.003
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could potentially greatly improve its prognosis in patients that were so far invariably condemned. Lastly, due to their availability as canine drugs, their apparent lack of toxicity in cats as well as their more appropriate spectrum of activity, other tyrosine kinase inhibitors targeting PDGFR specifically such as toceranib phosphate (Palladia, Zoetis, Belgium) and masitinib mesylate (Masivet and Kinavet, AB Science, France) may be promising alternative treatment options in feline HES.
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
References [1] Gotlib J, Cross NC, Gilliland DG. Eosinophilic disorders: molecular pathogenesis, new classification, and modern therapy. Best Pract Res Clin Haematol 2006;3:535—69. [2] Roufosse FE, Goldman M, Cogan E. Hypereosinophilic syndromes. Orphanet J Rare Dis 2007;2:37. [3] Isotani M, Tamura K, Yagihara H, et al. Identification of a c-kit exon 8 internal tandem duplication in a feline mast cell tumor case and its favorable response to the tyrosine kinase inhibitor imatinib mesylate. Vet Immunol Immunopathol 2006;114(1—2):168—72. [4] Lachowicz JL, Post GS, Brodsky E. A phase I clinical trial evaluating imatinib mesylate (Gleevec) in tumor-bearing cats. J Vet Intern Med 2005;19:860—4. [5] Valent P, Klion AD, Horny HP, et al. Contemporary consensus proposal on criteria and classification of eosinophilic disorders and related syndromes. J Allergy Clin Immunol 2012;130:607—12. [6] Simon HU, Rothenberg ME, Bochner BS. Refining the definition of hypereosinophilic syndrome. J Allergy Clin Immunol 2010;126:45—9.
[7] Simon D, Simon HU. Eosinophilic disorders. J Allergy Clin Immunol 2007;119(6):1291—300. [8] Malfuson JV, Fagot T, Konopacki J, Mangouka L, Souleau B, de Revel T. Hematological disorders and hypereosinophilia. Rev Med Interne 2009;4:322—30. [9] Guilhot F. Indications for imatinib mesylate therapy and clinical management. Oncologist 2004;3:271—81. [10] Ogbogu PU, Bochner BS, Butterfield JH, Glitch GJ, Huss-Marp J, Kahn JE, et al. Hypereosinophilic syndrome: a multicenter, retrospective analysis of clinical characteristics and response to therapy. J Allergy Clin Immunol 2009;6:1319—25. [11] Center SA, Randolph JF, Erb HN, Reiter S. Eosinophilia in the cat: a retrospective study of 312 cases (1975 to 1986). J Am Anim Hosp Assoc 1990;26:349—58. [12] Huibregtse BA, Turner JL. Hypereosinophilic syndrome and eosinophilic leukemia: a comparison of 22 eosinophilic cats. J Am Anim Hosp Assoc 1994;30:591—9. [13] Muller AM, Martens UM, Hofmann SC, Bruckner-Tuderman L, Bertelsmann R, Lübbert M. Imatinib mesylate as a novel treatment option for hypereosinophilic syndrome: two case reports and a comprehensive review of the littErature. Ann Hematol 2006;1:1—16. [14] Wilson SC, Thomson-Kerr K, Houston DM. Hypereosinophilic syndrome in a cat. Can Vet J 1996;37(11):679—80. [15] McEwen SA, Valli VE, Hulland TJ. Hypereosinophilic syndrome in cats: a report of three cases. Can J Comp Med 1985;3:248—53. [16] Lilliehook I, Tvedten H. Investigation of hypereosinophilia and potential treatments. Vet Clin North Am Small Anim Pract 2003;33(4):1359—78. [17] Takeuchi Y, Matsuura S, Fujino Y, Nakajima M, Takahashi K, Sakai Y, et al. Hypereosinophilic syndrome in two cats. J Vet Med Sci 2008;70(10):1085—9. [18] Muir P, Gruffydd-Jones TJ, Brown PJ. Hypereosinophilic syndrome in a cat. Vet Rec 1993;14:358—9. [19] Klion AD. Eosinophilic myeloproliferative disorders. Hematology Am Soc Hematol Educ Program 2011:257—63. [20] Klion AD, Bochner BS, Gleich GJ, Nutman TB, Gothenburg ME, Simon HU, et al. Approaches to the treatment of hypereosinophilic syndromes: a workshop summary report. J Allergy Clin Immunol 2006;6:1292—302.
Please cite this article in press as: Cochet Faivre N, et al. Three cases of feline hypereosinophilic syndrome treated with imatinib mesilate. Revue vétérinaire clinique (2014), http://dx.doi.org/10.1016/j.anicom.2014.10.003
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CLINICAL CASE
Three cases of feline hypereosinophilic syndrome treated with imatinib mesilate夽 Trois cas de syndrome hyperéosinophilique félin traités avec de l’imatinib mésylate N. Cochet Faivre a,∗,b,c, P. Prelaud a, E. Bensignor d,e,f, J. Declercq g, V. Defalque h a
Advetia, 5, rue Dubrunfaut, 75012 Paris, France Clinique vétérinaire des Halles, 28, Faubourd de Saverne, 67000 Strasbourg, France c Parasitology mycology dermatology-ENVA, 7, avenue Gal-de-Gaulle, 94704 Maisons-Alfort, France d Clinique vétérinaire, 6, rue Mare-Pavée, 35510 Rennes-Cesson, France e Clinique vétérinaire, 17, boulevard des Filles-du-Calvaire, 75003 Paris, France f Centre hospitalier vétérinaire, 22, rue Viviani, 44000 Nantes, France g Ghent university Salisburylaan, 133 9820 Merelbeke, Belgium h Department of clinical studies, Ontario veterinary college, university of Guelph, Guelph, Ontario, Canada b
Received 5 January 2014; accepted 23 October 2014
KEYWORDS Cat; Hypereosinophilic syndrome; Eosinophilic dermatitis; Imatinib mesylate; Tyrosine-kinase inhibitor
Summary A hypereosinophilic syndrome was diagnosed in three cats with refractory dermatitis and marked hypereosinophilia. The cats were treated with imatinib mesylate, a tyrosine-kinase inhibitor at the oral dose of 5 mg per cat. In all three cases, a dramatic improvement was rapidly observed. © 2014 Published by Elsevier Masson SAS on behalf of AFVAC.
夽 Crédits de formation continue. — La lecture de cet article ouvre droit à 0,05 CFC. La déclaration de lecture, individuelle et volontaire, est à effectuer auprès du CNVFCC (cf. sommaire). ∗ Corresponding author. E-mail address: [email protected] (N. Cochet Faivre).
http://dx.doi.org/10.1016/j.anicom.2014.10.003 2214-5672/© 2014 Published by Elsevier Masson SAS on behalf of AFVAC.
Please cite this article in press as: Cochet Faivre N, et al. Three cases of feline hypereosinophilic syndrome treated with imatinib mesilate. Revue vétérinaire clinique (2014), http://dx.doi.org/10.1016/j.anicom.2014.10.003
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MOTS CLÉS Chat ; Syndrome hyperéosinophilique ; Dermatite éosinophilique ; Imatinib mesilate ; inhibiteur des tyrosine-kinases
Résumé Un syndrome hyperéosinophilique est diagnostiqué chez 3 chats présentant une dermatite éosinophilique réfractaire à tout traitement et une hyperéosinophilie marquée. Les chats sont traités avec de l’imatinib dosée à 5 mg. Dans les trois cas, une amélioration spectaculaire est observée. © 2014 Publié par Elsevier Masson SAS pour l’AFVAC.
Introduction Imatinib is an oral chemotherapeutic agent that selectively inhibits the protein tyrosine-kinases Bcr-Abl, Kit and PDGFR (platelet-derived growth factor receptor) involved in oncogenesis. It has demonstrated remarkable clinical efficacy in human patients with chronic myeloid leukemia, malignant gastrointestinal stromal tumours, chronic eosinophilic leukemia and the hypereosinophilic syndrome (HES) [1,2]. It is currently marketed in several countries worldwide as its mesylate salt, imatinib mesylate (Gleevec or Glivec, Novartis, Switzerland). In veterinary medicine, imatinib is currently not registered for the treatment of animal diseases. It has however been used off-label for the treatment of canine and feline mast cell tumors as well as feline fibrosarcoma and squamous cell carcinoma [3,4]. The authors report here three cases of feline hypereosinophilic syndrome dramatically improved with imatinib mesylate. To our knowledge, the use of this drug for the treatment of feline HES has never been previously reported.
Case reports Case 1 A 6-year-old neutered male domestic shorthaired cat was referred to severe pruritic eosinophilic dermatitis of more than 5-year duration associated, since 2 months, with, inspire of treatment with steroids, worsening cutaneous and oral lesions, ptyalism, painful food prehension, weight loss and lethargy. The initial lesions were a linear granuloma located on the pelvic limbs and an eosinophilic plaque located on the inner thigh. A limited antigen diet trial (DR21 Royal Canin), flea control (fipronil + (S)-methoprene spot on, every month), antibiotic therapy (cefalexin, 20 mg/kg/BID), oral ciclosporin (7 mg/kg/day) and oral chlorambucil (2 mg/kg every three days) were of no benefit. Oral and injectable glucocorticosteroid therapy (prednisolone at 2 mg/kg/day, dexamethasone at 0.2 mg/kg/day, methylprednisolone acetate at 20 mg/month) had only led to a partial improvement during a few years. But two months prior to presentation, a severe deterioration was observed in spite of an injection of 20 mg methylprednisolone acetate and a prescription of dexamethasone at 0.2 mg/kg/day. On physical examination at the time of referral, the cat had lost over than 1 kg, (weight 4 kg) and was lethargic.
Figure 1. Clinical case 1: very large budding eroded oozing plaque on the right elbow.
The submandibular, retropharyngeal and prescapular lymph nodes were enlarged. Several cutaneous lesions were noted: a very large eroded oozing plaque with a central fistula located on the right elbow (Fig. 1), an eroded plaque on the left thoracic limb and an ulcer on the upper lips. The hard palate was painful, erythematous, eroded and punctuated by numerous white granulomas (Fig. 2). The other physical parameters were within normal limits. A complete blood count revealed an increased eosinophil count (4.77 × 109 /L, reference range 0.05—1.10 × 109 /L). On peripheral blood smear, mature eosinophilia was noted. The serum biochemical parameters were within normal limits. Serological and polymerase chain reaction tests were negative for feline leukaemia virus (FeLV), feline immunodeficiency virus (FIV), feline herpesvirus type 1 (FHV1) and calicivirus. Faecal floating examination was negative for intestinal parasites. Cytological examination of all mucosal and cutaneous lesions revealed the eosinophilic nature of the inflammation. Histopathological examination of the skin over the elbow revealed necrosis of the epidermis substituted by a necrotic coagulum, fragmented collagen fibers, eosinophilic dusting, picnotic cells (eosinophils?), the epidermic base is neovascularized and interspersed with inflammatory cells (mainly eosinophilic). Based on the findings, HES was diagnosed. Treatment was initiated with oral imatinib mesylate at a dose of 1.25 mg/kg
Please cite this article in press as: Cochet Faivre N, et al. Three cases of feline hypereosinophilic syndrome treated with imatinib mesilate. Revue vétérinaire clinique (2014), http://dx.doi.org/10.1016/j.anicom.2014.10.003
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Three cases of feline hypereosinophilic syndrome treated with imatinib mesilate
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glucocorticosteroid therapy was prescribed (methylprednisolone at 4 mg EOD). After 51 weeks, the owner reported a relapse in the cutaneous lesions and the lethargy. A complete blood count revealed hypereosinophilia (3.74 × 109 /L). Combination therapy was reintroduced and consisted of imatinib mesylate administered at a dose of 5 mg/day and methylprednisolone at a dose of 2 mg/day. After 59 weeks, a complete blood count revealed no abnormality. Cutaneous lesions had dramatically improved. The frequency of administration of both drugs was therefore decreased (imatinib mesylate 5 mg EOD and methylprednisolone 2 mg EOD). After 5 years of EOD imatinib mesylate — methylprednisolone combination therapy (imatinib mesylate 5 mg EOD and methylprednisolone 1 mg EOD), the cat is still alive. Peripheral hypereosinophilia and cutaneous lesions are controlled.
Case 2
Figure 2. Clinical case 1: erythematous, eroded hard palate punctuated by numerous eosinophilic granulomas.
Figure 3. Clinical case 1: cicatriz on the right elbow 16 weeks after initiating treatment with imatinib mesylate.
of body weight (i.e. 5 mg/day). Lesion improvement was noticeable after 4 weeks of treatment and a 90%-regression of all lesions was observed after 16 weeks (Fig. 3). Thanks to the regression of oral lesions, the patient gained over 1 kg. Peripheral blood eosinophilia returned to normal values after 10 weeks of treatment. After 17 weeks, imatinib mesylate was prescribed at a dose of 5 mg every other day (EOD). After 27 weeks, however, while the eosinophil count was within normal limits (0.2 × 109 /L), cutaneous lesions were again observed on both thoracic limbs as well as the upper lips. Combination therapy was started and consisted of orally administered dexamethasone at a dose of 0.2 mg/kg/day and imatinib mesylate, a dose of 5 mg EOD. Two weeks later, cutaneous lesions were controlled and imatinib mesylate was withdrawn. Maintenance
An 8-year-old neutered male strictly indoor domestic shorthaired was referred to a history of several months of pruritus, weight loss, partial anorexia and soft stools. Cutaneous lesions started on the head and had progressed to involve the neck, trunk and limbs. A limited antigen diet trial was unhelpful. Oral prednisolone (1 mg/kg/day) led to minor improvement. Histopathological examination of skin biopsies revealed a hyperplastic spongiotic eosinophilic dermatitis. On physical examination at the time of referral, the cat was very thin and weighed 2.4 kg. Skin lesions consisted of alopecia, erythematous erosions and crusts on the head, neck, dorsum and thoracic limbs (Fig. 4a,b). Abdominal palpation revealed thickened bowel loops. Multiple coat brushing and skin scraping were negative for ectoparasites. Cytological examination from skin lesions direct impression smears revealed eosinophilic inflammation. Complete blood count revealed leukocytosis (54.6 × 109 /L, reference range 5.5—15.5 × 109 /L) related to hypereosinophilia (10.9 × 109 /L). Eosinophils, on blood smear cytological examination, were mature and of normal morphology. The serum biochemical parameters were within normal limits. Abdominal ultrasonography confirmed the increased thickness of intestinal walls. Cytological examination of ultrasound-guided fine needle aspiration of the intestines revealed the presence of eosinophils. Based on these findings, HES was diagnosed and treatment with imatinib mesylate was initiated at 5 mg/day orally. Within 4 weeks, the skin lesions started to regress and the cat’s appetite improved. At two months, there was marked improvement of lesions. Unfortunately, a few weeks later, the patient was found dead, most likely after a hit by car accident.
Case 3 A 20-month-old neutered male domestic shorthaired cat was referred to a 14-month history of pruritus and dermatitis. The cutaneous lesions started on the face and had progressively generalized. Vomiting and lethargy were also noted.
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Figure 5. Clinical case 3: multifocal to coalescing erythematous, eroded, crusty papules and extended alopecia on the back.
Figure 4. Clinical case 2: alopecia, erythematous erosions and crusts on the face (a) and lateral view of the cat with localization of cutaneous lesions (b).
ultrasonography showed moderate hepatosplenomegaly and thickening of the intestinal walls. Tests for FeLV and FIV were negative. Based on these findings, HES was diagnosed. Treatment consisted of imatinib mesylate at a dose of 5 mg/day, orally. The cat was rechecked one and two months after the initiation of the treatment. At the first recheck, the condition of the cat had improved considerably, evidenced by the decrease in the pruritus and the size of the cutaneous lesions. At the next follow-up appointment, the pruritus had continued to decrease and all cutaneous lesions had resolved. Due to the cost of imatinib mesylate tablets, the owner declined further treatment and the cat was unfortunately lost to follow-up.
Discussion A limited antigen diet trial (DR21 Royal Canin), flea control (fipronil + (S)-methoprene spot on, every month),and antibiotic therapy (cefalexin 25 mg/kg BID) were inefficient. There was an initial improvement with orally administered dexamethasone 0.1 mg/kg/day but this medication lost its efficacy over time. Ciclosporin was then introduced orally (25 mg/day) with improvement after 30 days, however the disease worsened when the dose was tapered. On physical examination at the time of referral, the cat was thin (3 kg) and weak. Submandibular and popliteal lymph nodes were enlarged. Cutaneous lesions were predominantly located on the face, the dorsum and the abdomen. The cat had multifocal to coalescing erythematous, eroded, crusty papules and extensive alopecia (Fig. 5). Crusts and ulcers were noted on the margin of the pinnae. Focal, raised, erythematous, crusty eroded plaques were observed on the neck and the face. Two complete blood counts performed at a 2-week interval revealed hypereosinophilia ranging from 2.7 × 109 /L to 3.7 × 109 /L. On peripheral blood smear cytological examination, mature eosinophilia was noted. The serum biochemical parameters were within normal limits. Multiple skin scrapings were negative. Cytological examination from direct impression smears of skin lesions showed eosinophilic inflammation. Histopathological examination of skin biopsies revealed a superficial and deep, interstitial to perivascular, predominantly eosinophilic inflammation. Abdominal
In humans, the hypereosinophilic syndrome (HES) is defined as a heterogeneous group of rare diseases characterized by the presence of marked peripheral blood eosinophilia (greater than 1.5 × 109 /L), the absence of a secondary cause for the eosinophilia, and evidence of eosinophil-associated organ damage [5,6]. Recent techniques have allowed the characterization of human HES subtypes by their precise immunologic and genetic abnormalities. The two best described subtypes are the lymphocytic variant HES (L-HES), in which the underlying cause for the eosinophilia is the secretion of eosinophilopoietic cytokines by T lymphocytes, and myeloproliferative HES/chronic eosinophilic leukemia (CEL), most commonly caused by an interstitial deletion in chromosome 4 [2,7,8]. This deletion results in the creation of the Fip1like1-platelet-derived growth factor receptor-alpha gene fusion mutation (FIP1L1-PDGFR˛ or F/P +). This fusion gene encodes for a constitutively active tyrosine kinase, which was found to be responsible for the eosinophilia. These subtypes are associated with differences in clinical presentation, prognosis and responses to therapy. For example, although recognized as the more aggressive form of HES, F/P+ has become of much better prognosis thanks to the use of tyrosine kinase inhibitors [9]. The lymphocytic variant is, on the other hand, non-responsive to imatinib mesylate treatment [10].
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Three cases of feline hypereosinophilic syndrome treated with imatinib mesilate In the feline species, HES is defined as a rare disease of unknown aetiology that occurs primarily and is also characterized by persistent peripheral blood eosinophilia and organ infiltration by eosinophils that eventually cause organ failure [11]. Human HES tends to occur in patients aged from 20 to 50 years of age, although all age groups may be affected. A recent retrospective study reports a male/female ratio of 11/8 [10]. The F/P+ disease variant affects almost exclusively male patients. The age of affected cats ranges from 10 months to 12 years of age. A female predisposition has been observed in one study [12]. As described in humans, all cats reported in this study were males but our sample of three cats is too small to be representative. The organs most frequently involved in humans suffering from HES include the skin, the lungs, the heart, the nervous system and gastrointestinal tract, although virtually any tissue or organ can be infiltrated by eosinophils [2,6,10,13]. Dermatologic manifestations are non-specific and consist either in pruritus, urticaria, angioedema, erythroderma or in erythematous nodules or papules evocating eczema. Patients with L-HES often have a history of atopic disease and almost all of them present with cutaneous manifestations. Mucosal lesions can be observed. Gastrointestinal symptoms may include abdominal pain, diarrhea, nausea and vomiting. Non-specific symptoms including weakness, fatigue, anorexia, fever and weight loss are common. In cats, the most frequently involved organs are the gastrointestinal tract, the spleen and mesenteric lymph nodes [14,15]. Furthermore, the eosinophilic infiltration can also target the skin, the bone marrow, the liver, the lung, the heart or the pancreas [16]. The dermatologic lesions in the cases described here were non-specific and all three cats had different dermatological lesions and lesion distribution. One cat (case number 2) had concurrent gastrointestinal symptoms and cutaneous signs. Another patient had mucosal and cutaneous lesions and a history of pruritic dermatitis lasting for more than 5 years (case number 1). The HES is a diagnosis of exclusion, after clonal eosinophilia (evidenced by the presence of histologic, cytogenetic, or molecular clue of an underlying myeloid malignancy) and reactive eosinophilia (due to diseases such as parasitic or viral infections, drugs, allergic and autoimmune diseases, neoplasia, etc.) have been rigorously ruled out [2]. To date, routine investigations supporting the diagnosis of HES in cats are limited to history, clinical presentation, complete blood count and the exclusion of other recognizable causes for the eosinophilia [17]. Medical imaging is used to detect the involvement of internal organs. Histopathological examination of tissue samples are useful to confirm the eosinophilic nature of tissue infiltration. A myelogram is not necessary to establish the diagnosis of HES but is helpful when suspecting a myeloproliferative disorder. If left untreated, HES is progressively fatal. Glucocorticosteroids remain the mainstay of treatment for most human patients. Alternative therapies for patients failing or not tolerating glucocorticosteroid therapy include cytotoxic agents (such as hydroxyurea and vincristine) and immunomodulatory agents (including ciclosporin), of which interferon-␣ showed the most promise. Recent diagnostic advances and the development of novel targeted therapies, including the
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tyrosine kinase inhibitors and humanized monoclonal antibodies, have expanded the armamentarium [1,2,10]. The successful empiric treatment with imatinib mesylate in a human patient with HES refractory to traditional therapy was first reported in 2001. This patient achieved a rapid and complete haematologic remission rapidly after imatinib mesylate treatment initiation. Imatinib mesylate is currently the first line of treatment for patient with HES induced by F/P rearrangement [10]. So far, no successful therapy has been described in feline HES except in one case that was controlled with prednisolone and hydroxyurea for more than 28 months [18]. We elected for the empirical use of imatinib mesylate in the three cases reported here for several reasons. First, most cases of feline HES reported in the literature had a poor prognosis with a rapidly fatal disease course, despite all attempts of treatment. The mean survival expectation from time of diagnosis to death is of only 7.5 weeks [14]. Secondly, their disease was refractory to initial treatments with glucocorticosteroids, chlorambucil or ciclosporin. Third, the response to imatinib mesylate reported in certain human HES subtypes seemed promising to the authors. Furthermore, there is anecdotal evidence that imatinib mesylate is very well tolerated in cats. In one study, no signs of toxicity, as evaluated by complete blood count and serum biochemistry, were noted in 8 of the 9 tumor-bearing cats treated with imatinib mesylate, and minimal gastrointestinal toxicity (vomiting) was observed in one cat only [4]. Lastly, we obtained informed consent from the owners. At the time we treated our three patients with imatinib, both masitinib and toracenib were not commercially available and approved for use in veterinary medicine. In our patients, the daily dose of imatinib mesylate was 5 mg, varying from 1.25 to 2 mg/kg. In view of the absence of evidence-based recommendations in the veterinary literature outlining the efficient dose of oral imatinib mesylate in the feline species, this dose was chosen arbitrarily. Human studies have shown that the average oral imatinib dose is between 100 mg and 400 mg per patient or 1.25—5.7 mg/kg (based on a body weight of 70 kg) [19]. Long-term tolerance was excellent in the case number 1; no haematological or biochemical abnormalities were observed after five years of treatment. In cases number 2 and 3, short-term tolerance was satisfying, but long-term follow-up was not feasible. As previously described in humans, treatment discontinuation was followed two months later by recurrence of the disease in case number 1 [2,20]. The disease rapidly improved within two months of treatment renewal. In this patient, the persistence of cutaneous lesions prompted the reintroduction of oral methylprednisolone in combination with imatinib mesylate in order to control clinical lesions. Such combination therapy is described in the human literature [13].
Conclusion The amazing improvement with imatinib mesylate in these patients and its excellent tolerance after five years of empirical treatment in one of them suggest that this drug is useful in the treatment of feline hypereosinophilic syndrome and
Please cite this article in press as: Cochet Faivre N, et al. Three cases of feline hypereosinophilic syndrome treated with imatinib mesilate. Revue vétérinaire clinique (2014), http://dx.doi.org/10.1016/j.anicom.2014.10.003
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could potentially greatly improve its prognosis in patients that were so far invariably condemned. Lastly, due to their availability as canine drugs, their apparent lack of toxicity in cats as well as their more appropriate spectrum of activity, other tyrosine kinase inhibitors targeting PDGFR specifically such as toceranib phosphate (Palladia, Zoetis, Belgium) and masitinib mesylate (Masivet and Kinavet, AB Science, France) may be promising alternative treatment options in feline HES.
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
References [1] Gotlib J, Cross NC, Gilliland DG. Eosinophilic disorders: molecular pathogenesis, new classification, and modern therapy. Best Pract Res Clin Haematol 2006;3:535—69. [2] Roufosse FE, Goldman M, Cogan E. Hypereosinophilic syndromes. Orphanet J Rare Dis 2007;2:37. [3] Isotani M, Tamura K, Yagihara H, et al. Identification of a c-kit exon 8 internal tandem duplication in a feline mast cell tumor case and its favorable response to the tyrosine kinase inhibitor imatinib mesylate. Vet Immunol Immunopathol 2006;114(1—2):168—72. [4] Lachowicz JL, Post GS, Brodsky E. A phase I clinical trial evaluating imatinib mesylate (Gleevec) in tumor-bearing cats. J Vet Intern Med 2005;19:860—4. [5] Valent P, Klion AD, Horny HP, et al. Contemporary consensus proposal on criteria and classification of eosinophilic disorders and related syndromes. J Allergy Clin Immunol 2012;130:607—12. [6] Simon HU, Rothenberg ME, Bochner BS. Refining the definition of hypereosinophilic syndrome. J Allergy Clin Immunol 2010;126:45—9.
[7] Simon D, Simon HU. Eosinophilic disorders. J Allergy Clin Immunol 2007;119(6):1291—300. [8] Malfuson JV, Fagot T, Konopacki J, Mangouka L, Souleau B, de Revel T. Hematological disorders and hypereosinophilia. Rev Med Interne 2009;4:322—30. [9] Guilhot F. Indications for imatinib mesylate therapy and clinical management. Oncologist 2004;3:271—81. [10] Ogbogu PU, Bochner BS, Butterfield JH, Glitch GJ, Huss-Marp J, Kahn JE, et al. Hypereosinophilic syndrome: a multicenter, retrospective analysis of clinical characteristics and response to therapy. J Allergy Clin Immunol 2009;6:1319—25. [11] Center SA, Randolph JF, Erb HN, Reiter S. Eosinophilia in the cat: a retrospective study of 312 cases (1975 to 1986). J Am Anim Hosp Assoc 1990;26:349—58. [12] Huibregtse BA, Turner JL. Hypereosinophilic syndrome and eosinophilic leukemia: a comparison of 22 eosinophilic cats. J Am Anim Hosp Assoc 1994;30:591—9. [13] Muller AM, Martens UM, Hofmann SC, Bruckner-Tuderman L, Bertelsmann R, Lübbert M. Imatinib mesylate as a novel treatment option for hypereosinophilic syndrome: two case reports and a comprehensive review of the littErature. Ann Hematol 2006;1:1—16. [14] Wilson SC, Thomson-Kerr K, Houston DM. Hypereosinophilic syndrome in a cat. Can Vet J 1996;37(11):679—80. [15] McEwen SA, Valli VE, Hulland TJ. Hypereosinophilic syndrome in cats: a report of three cases. Can J Comp Med 1985;3:248—53. [16] Lilliehook I, Tvedten H. Investigation of hypereosinophilia and potential treatments. Vet Clin North Am Small Anim Pract 2003;33(4):1359—78. [17] Takeuchi Y, Matsuura S, Fujino Y, Nakajima M, Takahashi K, Sakai Y, et al. Hypereosinophilic syndrome in two cats. J Vet Med Sci 2008;70(10):1085—9. [18] Muir P, Gruffydd-Jones TJ, Brown PJ. Hypereosinophilic syndrome in a cat. Vet Rec 1993;14:358—9. [19] Klion AD. Eosinophilic myeloproliferative disorders. Hematology Am Soc Hematol Educ Program 2011:257—63. [20] Klion AD, Bochner BS, Gleich GJ, Nutman TB, Gothenburg ME, Simon HU, et al. Approaches to the treatment of hypereosinophilic syndromes: a workshop summary report. J Allergy Clin Immunol 2006;6:1292—302.
Please cite this article in press as: Cochet Faivre N, et al. Three cases of feline hypereosinophilic syndrome treated with imatinib mesilate. Revue vétérinaire clinique (2014), http://dx.doi.org/10.1016/j.anicom.2014.10.003