Elsevier

Leukemia Research

Volume 36, Issue 2, February 2012, Pages 192-197
Leukemia Research

Use of pegylated interferon in hypereosinophilic syndrome

https://doi.org/10.1016/j.leukres.2011.09.026Get rights and content

Abstract

Scant information exists about pegylated interferons (PEG-IFNs) use for treating hypereosinophilic syndrome (HES). We describe 6 patients with HES—1 patient with a newly identified chromosomal abnormality—who received PEG-IFNs. PEG-IFN alpha-2b replaced interferon (IFN) alpha-2b for 4 patients and was initial treatment of 2 patients. PEG-IFN alpha-2a was substituted when PEG-IFN alpha-2b became unavailable. PEG-IFNs were well tolerated and controlled eosinophilia. The dose of PEG-IFNs often could be tapered and the interval between doses lengthened beyond 7 days. Adverse effects included dose-related increases in liver enzyme levels, hair loss, mild lymphopenia, and neutropenia. PEG-IFNs are effective treatment of HES.

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)

  • R.M. Zielinski et al.

    Interferon-alpha for the hypereosinophilic syndrome

    Ann Intern Med

    (1990)
  • S. Fruehauf et al.

    Sustained remission of idiopathic hypereosinophilic syndrome following alpha-interferon therapy

    Acta Haematol

    (1993)
  • S. Ceretelli et al.

    Interferon-alpha in the idiopathic hypereosinophilic syndrome: consideration of five cases

    Ann Hematol

    (1998)
  • T.Y. Yoon et al.

    Complete remission of hypereosinophilic syndrome after interferon-alpha therapy: report of a case and literature review

    J Dermatol

    (2000)
  • O. Yamada et al.

    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

    (1998)
  • M. Kobayashi et al.

    Interferon-alpha therapy in the myeloproliferative variants of hypereosinophilic syndrome

    Rinsho Ketsueki

    (1993)
  • P.L. Bockenstedt et al.

    Alpha-interferon treatment for idiopathic hypereosinophilic syndrome

    Am J Hematol

    (1994)
  • L. Baratta et al.

    Favorable response to high-dose interferon-alpha in idiopathic hypereosinophilic syndrome with restrictive cardiomyopathy: case report and literature review

    Angiology

    (2002)
  • P.B. Hansen et al.

    Hypereosinophilic syndrome treated with alpha-interferon and granulocyte colony-stimulating factor but complicated by nephrotoxicity

    Am J Hematol

    (1993)
  • J.H. Butterfield et al.

    Interferon-alpha treatment of six patients with the idiopathic hypereosinophilic syndrome

    Ann Intern Med

    (1994)
  • Cited by (15)

    • HES and EGPA: Two Sides of the Same Coin

      2023, Mayo Clinic Proceedings
    • Biological Therapies of Immunologic Diseases: Strategies for Immunologic Interventions

      2017, Immunology and Allergy Clinics of North America
      Citation Excerpt :

      A subsequent study by the same group showed success in the treatment of chronic hepatitis B infection with parenteral IFN-α.30 Recombinant forms of IFN-α are currently used to treat hepatitis B and C, various cancers, and subsets of patients with hypereosinophilic syndromes.31,32 IFN-β was initially used in the 1980s, when human fibroblast IFN-β administered via lumbar puncture to 10 multiple sclerosis patients resulted in improvement,33 and this cytokine, in various forms, is still used in multiple sclerosis therapy.31

    • Eosinophilic Myocarditis

      2017, American Journal of the Medical Sciences
      Citation Excerpt :

      Commonly used options for steroid-refractory disease, or patients requiring steroid-sparing therapy, include cytoreductive therapy with hydroxyurea and interferon-α, single agent or in combination, as well as other immunosuppressive agents such as cyclosporine. Interferon-α is well known to cause side effects including myalgias, flu-like symptoms, depression and elevated liver enzymes, and the introduction of pegylated interferon-α in 2001 has greatly improved the tolerability of this treatment modality.55 The mechanism of action of interferon-α in HES is not completely understood but likely involves multiple pathways including inhibition of eosinophilopoetic cytokine production by T-lymphocytes and upregulation of interferon-γ production.56

    • How i treat hypereosinophilic syndromes

      2015, Blood
      Citation Excerpt :

      The most commonly used second-line therapies are hydroxyurea (1-2 g orally daily) and interferon-α (1-3 mU subcutaneously daily), each of which is effective in ∼30% of patients.14,16 Pegylated interferon has been used with equivalent results.83 Low-dose hydroxyurea (500 mg daily) has been reported to potentiate the effects of interferon-α without increasing toxicity in M-HES84,85 and is a reasonable alternative to escalating the interferon-α dose in HES patients who demonstrate partial response to interferon-α alone.

    • Management of Hypereosinophilic Syndromes

      2015, Immunology and Allergy Clinics of North America
      Citation Excerpt :

      Besides flu-like symptoms, side effects that should be monitored include depression, hepatotoxicity, autoimmunity, and thyroid gland dysfunction. Pegylated interferon may have equivalent efficacy and be better tolerated, and has been used both as switch-over treatment from nonpegylated forms of interferon-α and as initial treatment.47 IM is a second-line alternative for corticosteroid-refractory patients and those with features of chronic myeloproliferative disease.48

    • Eosinophilia in mast cell disease

      2014, Immunology and Allergy Clinics of North America
      Citation Excerpt :

      In the paper with the largest database of published HES patients from 2009, 20% of patients without myeloproliferative variant HES or chronic eosinophilic leukemia (CEL) had elevated tryptase levels (66% of the patients total had tryptase levels checked during workup in this population).13 Idiopathic HES can be α-interferon-responsive,14 something that is also used to control systemic mastocytosis in more severe cases.15 FIP1L1/PDFGRA-positive HES, described in 2003, also variably called myeloproliferative HES versus CEL, is the most significant entity in which an aberrant population of eosinophils is found with increased numbers of mast cells.

    View all citing articles on Scopus
    View full text