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Prepublished online as a Blood First Edition Paper on December 27, 2002; DOI 10.1182/blood-2002-10-3103.
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Divisions of Hematology and Internal Medicine,
Hematopathology, and Laboratory Medicine and Pathology, Mayo Clinic,
Rochester, MN; and Wessex Regional Genetics Laboratory, Salisbury
District Hospital, Salisbury, United Kingdom.
Imatinib mesylate (Gleevec), a small molecule inhibitor of abl,
kit, and platelet-derived growth factor receptor (PDGFR) tyrosine kinases, has been reported to be effective in the treatment of hypereosinophilic syndrome (HES) and a rare eosinophilia-associated chronic myeloid disorder (eos-CMD) characterized by the
t(5;12)(q33;p13) cytogenetic abnormality. In the current study, we
sought to confirm the preliminary observations in HES as well as
evaluate the therapeutic value of imatinib in eos-CMD that is not
associated with t(5;12)(q33;p13). Five patients with HES (all men,
median age = 46 years) and 2 with eos-CMD (both men, aged 45 and 58 years) were treated with imatinib at a starting dose of
100 to 400 mg/day. Cytogenetic studies showed no evidence of either the
bcr-abl translocation or t(5;12)(q33;p13) in any patient. Screening of
exons encoding the intracellular catalytic domains and extracellular
ligand binding domains of PDGFR Chronic, nonreactive eosinophilia characterizes the
hypereosinophilic syndrome (HES) as well as a spectrum of other clonal hematopoietic diseases associated with eosinophilia. In clonal eosinophilic disorders, the eosinophils can be demonstrated to be
either part of the malignant clone1,2 or produced as a result of cytokine production by the malignant clone.3-6
Imatinib mesylate (Gleevec), a small molecule that inhibits signal
transduction via tyrosine kinase oncoproteins including bcr-abl and
receptors for stem cell factor (c-kit) and platelet-derived growth
factor receptor (PDGFR), has recently been shown to be efficacious for the treatment of HES.7-9 In addition, imatinib has been
shown to be effective in chronic myeloid disorders (CMDs) associated with eosinophilia and rearrangement of the PDGFR Patients
Study design
All patients underwent baseline bone marrow biopsy with cytogenetics.
Presence of the bcr-abl translocation was excluded by fluorescence in
situ hybridization (FISH). Three of 5 patients with HES were screened
for clonal T-cell-receptor (TCR) gene rearrangement by
polymerase chain reaction (PCR) and/or Southern blot assays. Six of 7 patients were screened for mutations in coding exons of c-kit and
PDGFR Patients were started at a dose of 100 to 400 mg imatinib orally, taken once a day with food. Although the starting dose was determined at the discretion of the treating investigator, all patients were treated at the 400 mg/day dose if no response was observed at lower doses. Patients had regular physical examinations and evaluations of performance status, body weight, complete blood count, serum chemistry, chest X-ray, and cardiac echocardiography. Other imaging studies, including standard computed tomographic (CT) scans, radionuclide bone scans, and skeletal radiographic surveys, were performed as indicated, for assessing symptoms. Mutation analysis Genomic DNA isolated from either peripheral blood or bone marrow mononuclear cells as well as from purified eosinophil cell fractions from 6 patients was used in the mutational analysis (DNA was not available from case 4). PCR primers (sequences available on request) were designed to intronic sequence 50 to 100 bp away from the intron/exon boundary to detect any mutations that might affect splicing. All exons encoding the intracellular catalytic domains and extracellular ligand binding domains of PDGFR (exons 2-23) and c-kit
(exons 1-21) were amplified from patient genomic DNA using Amplitaq
Gold (Applied Biosystems, Foster City, CA). Products were then mixed
with an equal quantity of amplified DNA from human placental DNA. The
samples were denatured at 95°C and then slowly re-annealed by
reducing the temperature by 1.5°C every minute to room temperature.
The heteroduplexes of patient and normal DNA were then analyzed by
denaturing high-performance liquid chromatography (dHPLC WAVE;
Transgenomics, Crewe, United Kingdom). Melting temperatures for each
amplicon were calculated using Transgenomic Wavemaker v4.1 software.
The WAVE profiles for each patient were compared with the normal DNA,
and any patients with extra peaks (suggesting mismatches) or shifted
peaks (suggesting insertion or deletion of a few bases) were directly
sequenced on an ABI 377 Prism DNA sequencer (Applied Biosystems).
Hypereosinophilic syndrome Case 1.
A 46-year-old man presented with a constellation of symptoms that
included dyspnea, cough, night sweats, low-grade fever, skin lesions
with pruritus, and patchy and migratory numbness in the lower
extremities. Evaluation revealed leukocytosis
(15.5 × 109/L) with eosinophilia
(7.65 × 109/L) (Table 1),
left tibial mononeuropathy, and duodenal eosinophilic enteritis. A bone
marrow biopsy revealed increased numbers of mature eosinophils. He had
previously received 2 courses of pulse steroids with partial transient
symptomatic improvement. After discontinuation of corticosteroid
therapy, he was started on imatinib at a daily dose of 100 mg.
Case 2. A 32-year-old man presented with a 24-month history of a progressive skin rash that began as small erythematous papules on the extremities but gradually evolved to a diffuse erythroderma associated with scaling. Response to pulse steroid therapy was transient with prompt relapse of the rash after steroid taper or cessation. Several months prior to presentation at Mayo Clinic, the patient developed intermittent and occasionally high-grade fevers, weight loss, generalized lymphadenopathy, splenomegaly, and abnormal liver function tests. A left axillary lymph node biopsy was consistent with CD20+, Epstein-Barr virus-associated B-cell lymphoproliferative disorder, and consequently chemo-immunotherapy with a combination of rituximab plus CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone; R-CHOP) was started. The patient received 8 courses of R-CHOP with reduction of skin rash, lymphadenopathy, and splenomegaly, but 1 month after completion of this therapy, the skin rash and lymphadenopathy recurred. At this time, leukocytosis with eosinophilia was noted (Table 1) as well as progressive upper-lobe pulmonary consolidation on chest X-ray. After recovery from a Staphylococcus aureus skin infection with septicemia that required 6 weeks of antibiotic therapy, the patient underwent fiberoptic bronchoscopy with bronchoalveolar lavage and transbronchial lung biopsy and right axillary lymph node biopsy. The lung biopsy was consistent with chronic eosinophilic pneumonia, and the lymph node biopsy revealed an atypical lymphohistiocytic infiltrate with eosinophils. Given the progressive increase in peripheral eosinophil count associated with infiltration of lungs, lymph nodes, and possibly skin with eosinophils, the diagnosis of hypereosinophilic syndrome was made, and therapy with imatinib was initiated at the dose of 400 mg/day. The patient experienced prompt symptomatic improvement, with decreased cough and dyspnea, and decreased skin erythema and desquamation within the first week of imatinib therapy. By day 7 of therapy, both leukocyte and eosinophil counts had decreased from 17.8 × 109/L to 13.3 × 109/L and 10.0 × 109/L to 7.4 × 109/L, respectively, and a follow-up chest X-ray revealed significant clearing of his bilateral upper lobe pulmonary infiltrates. At last follow-up, 8 months after starting imatinib, the patient was in complete clinical remission and working full time. He had regained approximately 50 of the 70 lb of weight he had lost because of illness, and a follow-up chest X-ray and CT scan revealed complete resolution of the lung infiltrates. The dose of imatinib was empirically decreased to 300 mg/day at this time, although the patient tolerated the 400 mg/day dose without any toxicity.Case 3. A 24-year-old man presented with a long history of an acneiform skin rash involving his face and trunk and a several year history of relatively frequent upper respiratory tract, particularly sinus, infections, requiring antibiotic therapy. Three months prior to his Mayo Clinic presentation, leukocytosis and eosinophilia (Table 1) were incidentally noted during evaluation for an episode of "bronchitis." He also had intermittent epigastric pain and low-grade fevers at this time. Evaluation revealed iron-deficiency anemia, but an esophagogastroduodenoscopy (EGD) with biopsies did not reveal evidence of eosinophilic gastritis or enteritis. A bone marrow aspirate and trephine biopsy confirmed absent iron stores and further revealed prominent eosinophilia, with mature eosinophils comprising 35% to 40% of all nucleated marrow cells. He was treated with prednisone at the dose of 20 mg/day for several weeks without any decrease in the peripheral eosinophil count. After tapering and discontinuation of corticosteroid treatment, the patient was started on imatinib at the dose of 100 mg/day. A decline in peripheral leukocytosis and eosinophilia was promptly noted (within 1 week). The decline was gradual, but progressive, and at 8-week follow-up, the white blood count and eosinophil count had declined from 42.2 × 109/L to 22.4 × 109/L and from 32.5 × 109/L to 15.5 × 109/L, respectively. He was clinically stable and tolerating treatment well, and imatinib was escalated to 400 mg/day. He developed mild fatigue on the increased dose of imatinib, and at last-follow-up, while a further decline in the eosinophil count had been documented (Table 1), the higher dose of imatinib had only modest additional benefit.Case 4. A 50-year-old man developed progressive and eventually intractable, generalized skin pruritus that started 2 years prior to his Mayo Clinic presentation. The pruritus became more severe in the 6 months immediately prior to presentation, and, despite therapeutic trials with numerous agents, symptomatic benefit was consistently achieved only with prednisone. Unfortunately, however, the skin condition promptly relapsed on tapering of the corticosteroid, and he was consequently maintained on prednisone for a period of 9 months. In the year prior to presentation, eosinophilia had been noted (range, 8%-28% on the white blood count differential, while on prednisone therapy), but several skin biopsies had been unrevealing in terms of a specific diagnosis. The patient was noted to have excoriations and prurigo nodularis with pigmentation over the scalp, face, trunk, sacral area, buttocks, and proximal extremities on physical examination. Further evaluation revealed peripheral blood and marrow eosinophilia (Table 1), with maturing eosinophils and eosinophilic precursors accounting for 20% to 25% of bone marrow cellularity. A markedly elevated immunoglobulin E (IgE) level was also noted (9585.0 kU/L; mean, 13.2; +1 SD, 41.0; +2 SD, 127.0). The patient was started on imatinib at the dose of 100 mg/day. Although an approximately 40% decline was noted in the peripheral eosinophil count (Table 1), the patient experienced profound fatigue (grade 3) and elected to stop imatinib after 4 weeks of therapy.Case 5.
A 56-year-old man presented with a 5-year history of intensely pruritic
skin nodules and intermittent debilitating headaches. The former
initially appeared on the trunk and abdomen and later involved his
proximal extremities. Peripheral eosinophilia was first noted 4 years
ago (white blood cell count 16.3 × 109/L with 30%
eosinophils), and a detailed evaluation, including bone marrow and skin
biopsies, was unrevealing except for peripheral eosinophilia and
elevated IgE (25 360 kU/L; mean, 13.2; +1 SD, 41.0; +2 SD, 127.0). The
etiology of his headaches remained indeterminate despite multiple
imaging studies. Three years prior to presentation, the patient was
started on prednisone (80 mg/day), with prompt improvement of his skin
lesions and headaches and a decrease in the peripheral eosinophil
count. Unfortunately, however, both the skin lesions and headaches
relapsed on tapering of the corticosteroid, and he has been
consequently maintained on variable doses of prednisone since then. The
patient also received interferon- Eosinophilia-associated chronic myeloid disorders (eos-CMD) Case 6. A 45-year-old man had a 20-year history of untreated eosinophilia, during which time his only complaints were a chronic cough, which responded to inhaled bronchodilator therapy, and gout, which required treatment with allopurinol and colchicine. In the year immediately preceding his presentation at Mayo Clinic, the patient had experienced a rapid clinical decline, with increasing fatigue, bone pain, weight loss (35 lb), and progressive anemia and splenomegaly (spleen crossed the midline by 3 cm at the umbilicus). The pain and fatigue had most recently left the patient largely bed-bound. Initial evaluation revealed anemia, thrombocytopenia, and leukocytosis with eosinophilia and a leukoerythroblastic picture (Table 1). The bone marrow aspirate and trephine biopsy revealed a hypercellular marrow with decreased numbers of erythroid precursors and megakaryocytes, but an expanded granulocytic pool with eosinophilia and left-shifted maturation. Reticulin fibers were modestly increased (grade 1+) and a slight increase in CD34+ blasts was noted. Cytogenetic studies revealed a normal karyotype. The aggregate findings were suggestive of an eos-CMD associated with myelofibrosis. The patient was started on imatinib therapy at the dose of 100 mg/day. The patient had a dramatic response to therapy that was manifest both clinically, and by decreasing eosinophilia, within a week of starting treatment. At re-evaluation (12 weeks), the patient was clinically asymptomatic and reported a dramatic increase in his energy level and stamina. He had gained 9 kg in weight, and the spleen tip was no longer convincingly palpable on physical examination. Laboratory testing revealed improved hemoglobin concentration and platelet count, as well as complete resolution of the eosinophilia and leukoerythroblastic picture (Table 1). A follow-up bone marrow examination revealed a dramatic decrease in overall cellularity and resolution of eosinophilia (Figure 2). The patient at last follow-up continued to be in clinical and histologic remission.
Case 7. A 58-year-old man presented with a several-month history of progressive fatigue, weight loss, and abdominal pain from a rapidly enlarging spleen. He was found to have significant anemia, thrombocytopenia, a leukoerythroblastic picture (Table 1), and splenomegaly (spleen crossed the midline) on physical examination. An initial bone marrow biopsy was inadequate but was thought to be consistent with agnogenic myeloid metaplasia, and the patient received supportive care. He remained transfusion dependent despite erythropoietin support, and a presumptive diagnosis of pure red cell aplasia (PRCA) was made on the basis of absent erythroid precursors on the initial bone marrow study. The patient was started on hydroxyurea therapy for progressive symptomatic splenomegaly, and he did relatively well on this treatment (stable dose of 500 mg/day) for 3 to 4 months, at which time he had abrupt onset of fevers with rigors and developed acute pulmonary edema. Peripheral eosinophilia was noted at this time, and a repeat bone marrow aspirate and trephine biopsy showed a hypercellular marrow with increased granulocytic precursors and marked eosinophilia. Megakaryocytes were noted to be increased and present in clusters, and a focal increase in reticulin fibers was noted (grade 2+). Cytogenetic studies revealed trisomy 8, and a diagnosis of chronic eosinophilic leukemia with myelofibrosis associated with eosinophilic endomyocarditis was made. The patient was treated with pulse corticosteroids and continued on hydroxyurea (500 mg/day), which decreased the eosinophilia and spleen size. He did not, however, tolerate discontinuation of the steroids and was continued on a maintenance dose of 30 mg/day prednisone. The patient was also treated with cyclosporine for 3 months (in combination with steroids and hydroxyurea) on an empiric basis for PRCA, without response. Three weeks after the discontinuation of his ongoing therapies, the patient was started on imatinib at the dose of 400 mg/day. The patient declined further clinically while on therapy with imatinib. He developed profound fatigue and lost more weight, and progressive hepatosplenomegaly was noted on physical examination. Similarly, there was no improvement in eosinophil count (Table 1); he remained transfusion dependent and was deemed to have failed imatinib therapy, and this agent was discontinued after 4 weeks of treatment.Mutational analysis Mutational analysis of c-kit and PDGFR genes for 6 patients revealed several previously described polymorphisms, and for case 3, a heterozygous C>G change at position 3496 (GenBank Accession no. J03278), which predicts Ser1047Cys. No
other potentially pathogenic changes were found in either gene.
We have previously reported the efficacy of imatinib mesylate for the treatment of 5 patients with HES.9 Here, we describe treatment responses of 5 additional patients with HES, and 2 patients with eos-CMD. This study confirms prior observations of the efficacy of imatinib for treatment of HES and potentially further extends the indications for use of this agent for therapy of select cases of eos-CMD. Furthermore, in contrast to a prior report,9 our results suggest that serum IL-5 levels are not useful in distinguishing responders from nonresponders. Finally, a previously unrecognized, potentially life-threatening toxicity of imatinib, which may be specific for HES/eos-CMD patients, is described. Two patients with HES had a prompt and dramatic resolution of peripheral eosinophilia and are in complete clinical remission, and another patient has experienced a gradual and sustained ongoing partial response in terms of a decrease in the eosinophil count. One patient with HES had no decrease in eosinophilia, and treatment was abandoned in another because of drug toxicity. Although 1 of the 2 patients with eos-CMD had progressive disease despite imatinib therapy, the second had a prompt and dramatic response to treatment and remains in complete clinical and histologic remission at last follow-up. Constitutive activation of the PDGFR In our study, despite careful evaluation of 6 of 7 patients by bone
marrow (BM) cytogenetic analysis and screening of most coding
exons of c-kit and PDGFR An alternative hypothesis is that aberrant production of cytokines such as IL-3, IL-5, and granulocyte-macrophage colony-stimulating factor (GM-CSF) by an occult T-cell clone or by phenotypically abnormal but polyclonal T lymphocytes has been implicated in eosinophilopoiesis and eosinophil activation.3-6 Three of the 5 patients with HES were tested for presence of an occult T-cell clone by T-cell receptor gene rearrangement studies. Of these, only 1 patient (case 5; nonresponder to imatinib with a normal serum IL-5 level) had a detectable occult T-cell clone, confirmed by testing on 2 separate occasions in a 2-year interval. In this study, the serum IL-5 level was elevated in 3 patients with HES (all 3 responding patients) and in the patient with eosinophilia-associated atypical chronic myeloproliferative disorder, who also responded to imatinib (Table 1). This finding refutes the earlier suggestion that elevated serum IL-5 levels may predict for poor responses to imatinib treatment in patients with HES.9 This observation is consistent with the previously reported dramatic response to treatment of a single patient with eosinophilia-associated chronic myeloproliferative disorder, who had the t(5;12) translocation and elevated IL-5 levels.10 It should be stressed, however, that the demonstration of elevated serum IL-5 levels cannot be taken as conclusive evidence that eosinophilia is reactive, given the example of the above-mentioned case with elevated IL-5 levels in the presence of a clonal cytogenetic abnormality [t(5;12)] in myeloid cells. In addition, elevated levels of serum IL-6, another cytokine implicated in eosinophil production and activation, has been demonstrated in eos-CMD associated with specific clonal cytogenetic abnormalities.17,27 Although the exact role of c-kit-stem cell factor (SCF) signaling in the idiopathic hypereosinophilia syndromes is currently unclear, given the data that implicates this receptor-ligand pair in eosinophil adhesion, activation, and degranulation,28-30 we examined c-kit expression on marrow eosinophils by CD117 immunostaining of bone marrow sections for 4 of the 7 patients (cases 1, 2, 4, and 5). C-kit expression was not detected on eosinophils in any of these cases. Despite encouraging responses with imatinib in this study, and inearlier reports,7-9 the absence of both a specific cellular target for imatinib and a consistent cytogenetic abnormality has hindered the identification, in clinical practice, of those hypereosinophilic patients who are likely to benefit from imatinib therapy. Nevertheless, considering the commonly chronic and protracted clinical course of patients with primary eosinophilic disorders, and the relatively rapid decrease in the eosinophil count (days) in imatinib-responsive patients, a therapeutic trial of this drug is a useful intervention. Imatinib was relatively well tolerated in this study and was transiently withheld in 1 patient (case 1) for a previously unrecognized fulminant acute cardiac toxicity that patients with HES may be specifically susceptible to, and was discontinued in another (case 4) because of patient preference following development of worsening fatigue. Occult infiltration of the endomyocardium with eosinophils, which is not apparent by echocardiography, probably occurs in at least a subset of patients with HES, who are otherwise asymptomatic from the cardiac standpoint. For case 1, the time course of development of acute LV dysfunction after starting imatinib, the rapid response to corticosteroid therapy, and the histologic findings on endomyocardial biopsy, all suggest that inflammatory response to degranulation and/or lysis of infiltrating eosinophils has the potential to cause acute and fulminant cardiogenic shock. It is imperative that this potentially life-threatening complication be recognized early, because, as shown for case 1, the acute LV dysfunction may be reversible with prompt institution of corticosteroid therapy. In our practice, we now routinely perform serial echocardiograms in the first week of imatinib therapy, particularly in those patients in whom the eosinophilia shows a rapid response, to screen for preclinical onset of cardiac dysfunction. Although imatinib is clearly an active agent in HES and, as demonstrated in this report, other eosinophilia-associated chronic myeloid disorders, several crucial issues need further study. These issues include (1) the mechanism of imatinib activity at the molecular level remains unclear; and (2) the basis for heterogeneity of patients with HES, both in terms of the rate of decrease in eosinophil counts (eg, case 3 compared with cases 1 and 2) and the variable response to therapy, is also unclear.
We thank Gail Kephart for excellent technical assistance. We thank Novartis Pharmaceuticals (Basel, Switzerland) for providing the drug free of charge for patients on this study.
Submitted October 15, 2002; accepted December 17, 2002.
Prepublished online as Blood First Edition Paper, December 27, 2002; DOI 10.1182/blood-2002-10-3103.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Ayalew Tefferi, Division of Hematology and Internal Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905; e-mail: tefferi.ayalew{at}mayo.edu.
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 A. Tefferi, M. A. Elliott, and A. Pardanani Atypical Myeloproliferative Disorders: Diagnosis and Management Mayo Clin. Proc., April 1, 2006; 81(4): 553 - 563. [Abstract] [Full Text] [PDF]
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E. H. Stover, J. Chen, B. H. Lee, J. Cools, E. McDowell, J. Adelsperger, D. Cullen, A. Coburn, S. A. Moore, R. Okabe, et al. The small molecule tyrosine kinase inhibitor AMN107 inhibits TEL-PDGFR{beta} and FIP1L1-PDGFR{alpha} in vitro and in vivo Blood, November 1, 2005; 106(9): 3206 - 3213. [Abstract] [Full Text] [PDF]
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 A. A. Berlin and N. W. Lukacs Treatment of Cockroach Allergen Asthma Model with Imatinib Attenuates Airway Responses Am. J. Respir. Crit. Care Med., January 1, 2005; 171(1): 35 - 39. [Abstract] [Full Text] [PDF]
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A. Tefferi Blood Eosinophilia: A New Paradigm in Disease Classification, Diagnosis, and Treatment Mayo Clin. Proc., January 1, 2005; 80(1): 75 - 83. [Abstract] [PDF]
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A. Pardanani, S. R. Brockman, S. F. Paternoster, H. C. Flynn, R. P. Ketterling, T. L. Lasho, C.-L. Ho, C.-Y. Li, G. W. Dewald, and A. Tefferi FIP1L1-PDGFRA fusion: prevalence and clinicopathologic correlates in 89 consecutive patients with moderate to severe eosinophilia Blood, November 15, 2004; 104(10): 3038 - 3045. [Abstract] [Full Text] [PDF]
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A. Pardanani and A. Tefferi Imatinib targets other than bcr/abl and their clinical relevance in myeloid disorders Blood, October 1, 2004; 104(7): 1931 - 1939. [Abstract] [Full Text] [PDF]
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A. B. Dietz, L. Souan, G. J. Knutson, P. A. Bulur, M. R. Litzow, and S. Vuk-Pavlovic Imatinib mesylate inhibits T-cell proliferation in vitro and delayed-type hypersensitivity in vivo Blood, August 15, 2004; 104(4): 1094 - 1099. [Abstract] [Full Text] [PDF]
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 S. M Payne and M. J Kovacs Imatinib Mesylate Treatment in Two Patients with Idiopathic Hypereosinophilic Syndrome Ann. Pharmacother., July 1, 2004; 38(7): 1215 - 1218. [Abstract] [Full Text] [PDF]
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 F. Guilhot Indications for Imatinib Mesylate Therapy and Clinical Management Oncologist, June 1, 2004; 9(3): 271 - 281. [Abstract] [Full Text] [PDF]
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J. Gotlib, J. Cools, J. M. Malone III, S. L. Schrier, D. G. Gilliland, and S. E. Coutre The FIP1L1-PDGFR{alpha} fusion tyrosine kinase in hypereosinophilic syndrome and chronic eosinophilic leukemia: implications for diagnosis, classification, and management Blood, April 15, 2004; 103(8): 2879 - 2891. [Abstract] [Full Text] [PDF]
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 S.-G. Plotz, H.-U. Simon, U. Darsow, D. Simon, E. Vassina, S. Yousefi, R. Hein, T. Smith, H. Behrendt, and J. Ring Use of an Anti-Interleukin-5 Antibody in the Hypereosinophilic Syndrome with Eosinophilic Dermatitis N. Engl. J. Med., December 11, 2003; 349(24): 2334 - 2339. [Full Text] [PDF]
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V. Pitini, C. Arrigo, D. Azzarello, G. La Gattuta, C. Amata, M. Righi, S. Coglitore, A. Tefferi, and A. Pardanani Serum concentration of cardiac Troponin T in patients with hypereosinophilic syndrome treated with imatinib is predictive of adverse outcomes Blood, November 1, 2003; 102(9): 3456 - 3457. [Full Text] [PDF]
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A. Pardanani, R. P. Ketterling, S. R. Brockman, H. C. Flynn, S. F. Paternoster, B. M. Shearer, T. L. Reeder, C.-Y. Li, N. C. P. Cross, J. Cools, 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, November 1, 2003; 102(9): 3093 - 3096. [Abstract] [Full Text] [PDF]
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A. Tefferi, A. Pardanani, C.-Y. Li, A. D. Klion, C. Akin, and T. B. Nutman Hypereosinophilic syndrome with elevated serum tryptase versus systemic mast cell disease associated with eosinophilia: 2 distinct entities? Blood, October 15, 2003; 102(8): 3073 - 3074. [Full Text] [PDF]
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Top
Abstract
Introduction
at the dose of 3 to 5 MU/day
subcutaneously added to prednisone for a period of 9 months with little
added benefit. A subsequent workup revealed persistent peripheral and
bone marrow eosinophilia (Table 