Anti-IL-5 Therapy for Hypereosinophilic Syndrome (HES)
Abstract & Commentary
By Andrew Artz, MD, Division of Hematology/Oncology, University of Chicago, Chicago, IL. Dr. Artz reports no financial relationship to this field of study.
Synopsis: Hypereosinophilic syndrome (HES) is a spectrum of diseases where a primary cause of eosinophilia can not be identified. Interleukin-5 plays an essential role in eosinophilia and possibly mediates disease manifestations prompting evaluation of mepolizumab, an anti- IL-5 antibody monoclonal antibody in HES. Eighty-five HES patients that were negative for the FIP1L1-PDGFRA rearrangement and stable on prednisone monotherapy were randomized on a 1:1 placebo controlled trial. A reduction of prednisone therapy to 10 mg or less over 8 or more weeks was achieved by 84% receiving of patients receiving mepolizumab and 43% for those on placebo (HR= 2.9; 95% CI, 1.5 to 5.3; P<0.001). No significant difference was seen in serious adverse events. Mepolizumab is a novel agent showing clinical activity in FIP1L1-PDGFRA negative hypereosinophilic syndrome.
Source: M Rothenberg, et al, for the Mepolizumab HES Study Group. Treatment of patients with the hypereosinophilic syndrome with mepolizumab. NEJM. 2008;358:1215-1228.
Hypereosinophilic syndrome (HES) comprises a group of uncommon and heterogeneous conditions characterized by persistent idiopathic eosinophilia and organ related damage. Aside from the uniform hematologic involvement, manifestations in other organs are quite variable and may include cardiac, cutaneous, neurologic, pulmonary, hepatic, splenic, ocular, and gastrointestinal.1 The variable classification schemes reflect uncertainty in the underlying disease pathogenesis. Nevertheless, eosinophilic infiltration and inflammatory mediators appear directly responsible for organ damage leading to clinical sequelae.2 Traditional treatments have included non-specific therapies of hydoxyurea, steroids and/or interferon-alpha. Recent characterization of constitutively activated receptor tyrosine kinases in the myeloproliferative variant of HES has lead to trials documenting sustained and complete responses to imatinib.3 Specifically, a cryptic interstitial deletion pairing Fip1-like1 gene (FIP1L1) to the platelet-derived growth factor receptor alpha chain gene (PDGFRA) leads to a novel oncogenic protein. A subset of myeloproliferative HES without the FIP1L1-PDGFRA fusion also responds to imatinib, suggesting activation of other receptor tyrosine kinases.4 Interleukin-5 (IL-5) plays a central role in mediating peripheral blood eosinophilia in some types of HES and has thus emerged as an appealing therapeutic target.5,6 Mepolizumab is humanized, anti-interleukin-5 monoclonal antibody showing strong affinity for free IL-57 and preliminary data have suggested activity in HES.8
Based upon these data, Rothenberg and colleagues conducted a double-blind randomized study of adults with HES but negative for the FIP1L1-PDGFRA oncogene. Patients (n = 85) who were clinical stable on prednisone monotherapy were randomized in a 1:1 fashion to 750 mg of IV mepolizumab or placebo. Prednisone was then tapered and the need for rescue steroids assessed. The primary endpoint, reduction of prednisone dose to 10 mg per day for 8 consecutive weeks, occurred in 84% of the mepolizumab but only 43% in the placebo arm (HR= 2.9, P < 0.001). Only 12% of patients in the active arm withdrew due to lack of efficacy whereas 50% in the placebo cohort dropped out due to lack of efficacy. Peripheral blood eosinophilia fell to less then 600 K/uL for 8 consecutive weeks in 95% of the mepolizumab patients compared to 45% of placebo treated patients (P < 0.001). The change in quality of life scores over the study did not differ between treatment arms. Serious or non-serious adverse events also did not differ significantly by treatment arm. Seven mepolizumab patients had serious adverse events compared to five patients in the placebo group. Mepolizumab patients, however, stayed on study longer due to lower drop out rates.
Commentary
Eosinophilia is a relatively common problem in routine clinical practice. Most cases are secondary to other causes such as parasitic infection, allergic reaction, collagen vascular disease, or an underlying hematologic malignancy. The diagnosis of HES must be entertained once other causes have been excluded. The heterogeneous nature of HES makes diagnosis and management difficult. Excluding FIP1L1-PDGFRA fusion protein by Fluorescence In-Situ Hybridization (FISH), commonly found in the myeloproliferative variant, is essential because imatinib is the therapy of choice. In addition to anemia or thrombocytopenia, features suggestive of the myeproliferative variant include male gender, elevated serum B12, elevated serum tryptase, splenomegaly, mucosal ulceration, bone marrow dysplasia, and bone marrow fibrosis.
Considerable morbidity can result from HES both from the disease and from treatments such as steroids, hydroxyurea or interferon. In this study, for patients with FIP1L1-PDGFRA negative HES who usually are imatinib non-responsive, the investigators assessed the activity of mepolizumab, a novel anti-IL-5 antibody. As a primary mediator of eosinophilia, IL-5 is an obvious target. Mepolizumab showed significant activity. Patients on study drug were able to have the steroid doses markedly reduced while maintaining a low peripheral blood eosinophil count, a major goal of HES therapy. Thus, mepolizumab therapy promoted lower eosinophil counts and reduced steroid requirements. The mean serum IL-5 levels were in the normal range in most patients possibly related to pre-existing steroid therapy before randomization. Thus, it was not possible to determine the extent to which IL-5 reductions correlated with efficacy. Future studies in patients having active disease should monitor IL-5 levels to determine if reduction of free IL-5 is the primary mechanism of action and whether IL-5 levels can be used as a biomarker. Quality of life scores did not differ. The authors propose that this may be because those enrolled in this study were highly motivated and had an excellent baseline quality of life.
This well-designed study of HES is also emblematic of the hurdles of assessing benefits and toxicity for rare diseases. The planned steroid withdrawal is a reasonable strategy to demonstrate steroid sparing, and thus disease related activity. However, as the authors note, whether mepolizumab should be used for acute presentations of HES or patients not stabilized on steroids can not be answered. While promising, more data will be needed before mepolizumab can be recommended in HES, even for patients meeting the study criteria of stable disease on high-dose steroids. In addition, occasional patients without the FIP1L1-PDGFRA rearrangement are responsive to imatinib. Thus, future studies may need to exclude imatinib sensitivity, at least in those having features of the myeloproliferative variant of HES. The small sample size also prevents excluding uncommon but serious drug toxicities. This can not be overemphasized enough for phase II studies powered to show activity, rather then improved survival. One fatal cardiac arrest occurred in a patient on mepolizumab. While one might expect a heightened incidence of cardiac events in a disease impacting the heart, this further illustrates the importance of longer term follow-up and the need for diligent and uniform adverse assessment in subsequent studies. The authors note a long term follow-up trial is ongoing.
In conclusion, mepolizumab, a novel anti-IL-5 antibody has steroid sparing activity in hypereosinophilic syndromes without the FIP1L1-PDGFRA fusion protein and holds tremendous promise.
References
1. Fauci AS, et al. NIH conference. The idiopathic hypereosinophilic syndrome. Clinical, pathophysiologic, and therapeutic considerations. Ann Intern Med. 1982;97:78-92.
2. Weller PF, Bubley GJ. The idiopathic hypereosinophilic syndrome. Blood. 1994;83:2759-2779.
3. Gleich GJ, et al. Treatment of hypereosinophilic syndrome with imatinib mesilate. Lancet. 2002;359:1577-1588.
4. Cools J, et al. A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. N Engl J Med. 2003;348:1201-1214.
5. Roufosse F, et al. Recent advances in pathogenesis and management of hypereosinophilic syndromes. Allergy. 2004;59:673-689.
6. Schrezenmeier H, et al. Interleukin-5 is the predominant eosinophilopoietin produced by cloned T lymphocytes in hypereosinophilic syndrome. Exp Hematol. 1993;21:358-365.
7. Hart TK, et al. Preclinical efficacy and safety of mepolizumab (SB-240563), a humanized monoclonal antibody to IL-5, in cynomolgus monkeys. J Allergy Clin Immunol. 2001;108:250-257.
8. Plotz SG, et al. Use of an anti-interleukin-5 antibody in the hypereosinophilic syndrome with eosinophilic dermatitis. N Engl J Med. 2003;349:2334-2339.
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