Use of pegylated interferon in hypereosinophilic syndrome
Introduction
The first reports that the biologic response modifier interferon (IFN) alpha-2b could be a useful agent for the treatment of hypereosinophilic syndrome (HES) appeared more than 20 years ago [1], [2]. Since then, evidence has appeared in the medical literature regarding the ability of IFN alpha to control hypereosinophilia that is resistant to prednisone [3], [4], [5], hydroxyurea [6], [7], and the combination of prednisone and hydroxyurea [1], [2], [3], [8], [9], as well as various other agents singly and in combination [3], [4], [10], [11], [12]. The clinical spectrum of IFN alpha's effectiveness has been well documented. These findings include clinical and cytogenetic remission of HES in patients with diverse chromosomal abnormalities [6], [13], [14], [15] and resolution or improvement of organ system dysfunction, such as hepatomegaly [1], splenomegaly [2], [14], [16], hepatosplenomegaly [3], congestive heart failure [3], [6], pulmonary infiltrates [5], and dermatologic manifestations, including incapacitating mucosal ulcers [11], [16] and pruritic papules, nodules, and plaques [5], [17].
In vitro studies suggest that the action of IFN alpha in hypereosinophilic disorders is multifaceted. A functional receptor for IFN alpha is present on the eosinophils of patients with various eosinophilic disorders, although the percentage of receptor-positive eosinophils can range widely (from 20% to 86%) [18]. Hypereosinophilic patients receiving IFN alpha treatment have significant reductions in serum levels of eosinophil major basic protein [11], a clinical finding supported by in vitro studies in which preincubation of eosinophils with IFN alpha inhibited release of other secondary granule proteins, eosinophil-derived neurotoxin, and eosinophil cationic protein by eosinophils activated by immunoglobulin (Ig) A or IgE immune complexes [18]. IFN alpha also inhibits eosinophil colony growth by nonadherent, non-T bone marrow cells stimulated with either interleukin (IL)-5 or granulocyte-macrophage colony-stimulating factor [19]. Reduction of eosinophil numbers in this manner also serves to interrupt the autocrine loop through which the eosinophil's own production of IL-5 continuously increases terminal differentiation of eosinophil precursor cells [20]. In several in vitro systems, IFN alpha has been shown to inhibit production of eosinophil-active cytokines [21], [22], [23]. IFN also promotes development of TH1 cells, 1 product of which (IFN gamma) has diverse inhibitory effects on eosinophil differentiation and migration [24], [25], as well as promotion of apoptosis [26].
Pegylated interferon (PEG-IFN) is prepared by either chemical covalent conjugation of 1 molecule of branched methoxy polyethylene glycol (PEG) to lysine residues in the IFN molecule via urethane bonds (PEG-IFN alpha-2a) or covalent attachment of monomethoxy PEG to the secondary amine of the histidine-34 residue (PEG-IFN alpha-2b) [27]. In vitro PEG-IFN alpha-2a retains properties of IFN alpha, including receptor binding, signal transduction [28], and antiproliferative activity against human tumor cells [29]. The attachment of the 12,000-D monomethoxy PEG polymer to native IFN alpha-2b greatly increases serum half-life, enabling weekly administration [30]. PEG-IFN alpha-2b has been effective in controlling disease in a significant proportion of BCR-ABL-negative myeloproliferative disorders [31].
For IFN alpha-2b, the effective dose for HES ranges from 0.5 to 3.0 million units (MU) every other day to 6.25 MU daily [32]. Dosing guidelines for PEG-IFN use in HES are not well established. Treatment of patients having chronic myelocytic leukemia (CML) and patients having solid tumors with PEG-IFN alpha-2b at a dose of 6 μg/kg per week gave a safety profile comparable to a nonpegylated IFN alpha-2b dose of 3–5 MU/m2 per day [33]. For patients with hepatitis C, exposure to PEG-IFN at 0.25 μg/kg per week gave a similar exposure as non-PEG-IFN alpha-2b at a dose of 3 MU 3 times per week, based on observed area under the curve [33]. In another study of patients with hepatitis C, the incidence and severity of adverse events were similar among patients treated with PEG-IFN alpha-2b at 0.5 μg/kg per week and with non-PEG-IFN alpha-2b at 3 MU 3 times per week [34]. Treatment of 4 HES patients with PEG-IFN alpha-2b (exact dose not specified) (median dose, 1.5 μg/kg per week) resulted in 1 complete and 1 partial response [31]. Because the effectiveness of PEG-IFN in hypereosinophilic disorders has not been widely reported, we reviewed our experience with use of PEG-IFNs in 6 patients with HES.
Section snippets
Materials and methods
We evaluated 6 patients who met the current criteria for HES [35] who had received PEG-IFN in the course of therapy. After documenting an initial patient's successful response to PEG-IFN from 2004 to 2007 (patient 3 in the present series), we considered PEG-IFN to be of possible therapeutic benefit to our HES patients and we began to gradually introduce it into our practice for treating HES. The present report includes a retrospective review of our initial patient and 5 additional patients seen
Results
Abnormal findings on bone marrow examination of these 6 patients included slight to moderate hypercellularity (n = 5); increased eosinophil numbers (n = 6), including left-shifted eosinophil maturation (n = 3); and reduced granulopoiesis (n = 2). In no case was there evidence of a chronic myeloproliferative disorder, increased numbers of blasts, plasma cells, or findings of lymphoma. Features of systemic mastocytosis were not present in any specimen.
Table 1 summarizes the clinical and laboratory
Discussion and conclusions
The observations reported in the current series show that PEG-IFN alpha can be used to control eosinophilia in patients with HES. In the report of Jabbour et al. [31], 2 of 4 patients treated with PEG-IFN had complete or partial responses. Although the majority of reported series have used IFN alpha-2b to control eosinophilia, IFN alpha-2a, which differs from IFN alpha-2b by a single amino acid [36], also can induce complete hematologic and cytogenetic responses in HES [15]. We found that when
Role of the funding source
No sponsors were involved in support of this study.
Conflict of interest statement
The authors have no conflicts of interest to declare.
Acknowledgements
None.
Contributions: J.H.B. and C.R.W. were involved in conception and design of the study, acquisition of data, analysis and interpretation of data, drafting the article and revising it critically for important intellectual content, and final approval of the version to be submitted.
References (40)
- et al.
Alpha-interferon and hypereosinophilic syndrome with trisomy 8: karyotypic remission
Blood
(1995) - et al.
Eosinophils express a functional receptor for interferon alpha: inhibitory role of interferon alpha on the release of mediators
Blood
(1996) - et al.
Synthesis of interleukin-5 by activated eosinophils in patients with eosinophilic heart diseases
Blood
(1993) - et al.
Pegylated interferon-alfa-2a induces complete hematologic and molecular responses with low toxicity in polycythemia vera
Blood
(2008) Treatment of hypereosinophilic syndromes with prednisone, hydroxyurea, and interferon
Immunol Allergy Clin North Am
(2007)- et al.
A randomized, double-blind trial comparing pegylated interferon alfa-2b to interferon alfa-2b as initial treatment for chronic hepatitis C
Hepatology
(2001) - et al.
Refining the definition of hypereosinophilic syndrome
J Allergy Clin Immunol
(2010) - et al.
Historical review: cytokines as therapeutics and targets of therapeutics
Trends Pharmacol Sci
(2004) - et al.
Deletion of chromosome 20q associated with hypereosinophilic syndrome: a report of two cases
Cancer Genet Cytogenet
(1996) - et al.
Alfa-interferon in a case of hypereosinophilic syndrome
Br J Haematol
(1990)
Interferon-alpha for the hypereosinophilic syndrome
Ann Intern Med
Sustained remission of idiopathic hypereosinophilic syndrome following alpha-interferon therapy
Acta Haematol
Interferon-alpha in the idiopathic hypereosinophilic syndrome: consideration of five cases
Ann Hematol
Complete remission of hypereosinophilic syndrome after interferon-alpha therapy: report of a case and literature review
J Dermatol
Clinical and cytogenetic remission induced by interferon-alpha in a patient with chronic eosinophilic leukemia associated with a unique t(3;9;5) translocation
Am J Hematol
Interferon-alpha therapy in the myeloproliferative variants of hypereosinophilic syndrome
Rinsho Ketsueki
Alpha-interferon treatment for idiopathic hypereosinophilic syndrome
Am J Hematol
Favorable response to high-dose interferon-alpha in idiopathic hypereosinophilic syndrome with restrictive cardiomyopathy: case report and literature review
Angiology
Hypereosinophilic syndrome treated with alpha-interferon and granulocyte colony-stimulating factor but complicated by nephrotoxicity
Am J Hematol
Interferon-alpha treatment of six patients with the idiopathic hypereosinophilic syndrome
Ann Intern Med
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