Pegylated interferon alpha 2a is an effective and well‐tolerated treatment option for lymphocyte‐variant hypereosinophilic syndrome

The lymphocyte-variant hypereosinophilic syndrome (L-HES) is a clinical subtype of hypereosinophilic syndrome (HES) characterized by an aberrant T-lymphocyte population producing eosinophilopoetic cytokines such as interleukin-5 (IL-5) (Khoury, 2017). Corticosteroids are considered the first-line treatment for this rare disease, but many patients require second-line therapy due to inadequate response or high dose dependency. In a retrospective study of patients with various types of HES, those with L-HES had an odds ratio of 0·34 for response to corticosteroids compared to idiopathic HES (iHES) (Khoury et al., 2018). The largest series of L-HES patients with the classic CD3−CD4+ phenotype reported that the 18 patients treated with steroids required 10–25 mg of prednisone per day to maintain response (Lefevre et al., 2014). Interferon alpha, methotrexate, ciclosporin, hydroxycarbamide, imatinib and mepolizumab have all been used as second-line therapy, but the optimal treatment for steroid-refractory or resistant L-HES has not been established. For HES in general, small case series of patients with sustained response to both conventional and pegylated interferon (peg-IFN) alpha have been reported (Butterfield & Gleich, 1994; Butterfield & Weiler, 2012). Interferon alpha activates CD8 T and NK cells leading to suppression of Th2 activity and a decrease in IL-4 and IL-5. A retrospective study including 46 HES patients treated with conventional interferon demonstrated a 17% complete response rate with 87% discontinuation due to medication intolerance (Ogbogu et al., 2009). peg-IFN alpha is generally better tolerated than conventional interferon, with fewer side effects and once weekly administration. Moreover, the L-HES subtype may be more amenable to interferon therapy than other types of HES, as 7/8 patients with CD3−CD4+ L-HES treated with either conventional or peg-IFN had at least a partial response (Lefevre et al., 2014). In our centre, peg-IFN alpha 2a has been the preferred second-line therapy for patients with steroid-refractory or resistant L-HES since 2011. Given the relative paucity of literature about treatment of this rare disease, and the need for an effective, tolerable alternative to corticosteroids, we performed a retrospective analysis of nine consecutive patients with L-HES requiring systemic therapy, focusing on treatment outcomes with peg-IFN alpha 2a. All patients had clinical symptoms, immunophenotyping and T-cell clonality studies by polymerase chain reaction (PCR) consistent with L-HES, as well as extensive evaluation to exclude chronic eosinophilic leukemia and reactive causes of eosinophilia. Flow cytometry was performed on peripheral blood to identify the abnormal T-cells including the three most commonly recognized L-HES subtypes (normal range as % of total lymphocytes): CD3−4+(≤2%), CD3+CD4+CD7− (≤10%) and CD3+CD4−CD8− (≤15%). Two of the subjects have been previously published as individual case reports (L3 and L8; Cheung et al., 2018; Dou et al., 2019); our flow cytometry and T-cell clonality methods have been described in a previous publication (Carruthers et al., 2016). Response to treatment was defined as control of symptoms and eosinophils <1·0 × 109/l (Khoury et al., 2018). There were five males and four females; the median age at diagnosis was 55 years (range 22–91), and median follow up was 44 months (range 12–98). The most common symptom was skin involvement (7/9) including dermatitis, pustulosis, erythroderma, urticaria, and dermatographism. Lung involvement and lymphadenopathy were present in four and three patients respectively. Laboratory results are summarized in Table 1. Two patients (L3 and L7) had a strongly positive antinuclear antibody (ANA) test result of 26 and 14 units (normal <1) but did not meet diagnostic criteria for rheumatologic disease. All patients received first-line oral corticosteroids (Table 2). One patient (L1) has maintained a stable remission on chronic low dose prednisone (2·5 mg/day), and one (L9) has been in clinical remission since a short course of prednisone in 2010. The remaining seven patients either did not achieve an adequate response on corticosteroids alone, or had a high dose dependency (>10 mg/day or more, or a dose intolerable to the patient). These patients were treated with peg-IFN alpha 2a, starting at 45–90 µg sc weekly and increasing as tolerated to a maximum of 180 µg sc weekly. All of the patients had clinical improvement of symptoms and were able to decrease their steroid dose within one month of starting interferon. Six of seven patients treated with peg-IFN alpha 2a achieved sustained, steroid-free response for a median of 31 months (range 10–95 months). One of these patients (L7) required hydroxycarbamide in addition to peg-IFN alpha 2a 180 µg sc every two weeks before prednisone could be discontinued. One patient (L1) had brief response to peg-IFN alpha 2a for four months before her erythroderma relapsed and she subsequently responded well to oral mycophenolic acid 720 mg twice daily. The other six had a complete, steroid-free response with resolution of eosinophil-related end organ damage, and remain off steroids and in remission on peg-IFN alpha 2a at last follow up. None of the patients had adverse reactions such as elevation of liver function enzymes, cytopenias, flu-like symptoms, mood disturbance or hair loss requiring cessation of treatment or dose adjustment. Clinical summary (Study ID; date of diagnosis to date of last visit mm/yy) Eosinophils at diagnosis (109/l) Eosinophils at last visit (109/l); Flow cytometry at diagnosis (normal range; absolute lymphocytes, 109/l) Flow cytometry after treatment (normal range; absolute lymphocytes, 109/l) T cell receptor PCR IL-5 at diagnosis, pg/ml IL-5 at last visit, pg/ml Response to peg-IFN alpha 2a (time on treatment) 25·7% CD4+/7− (<10%; 0·9) L-HES is a unique subtypes of HES, distinct from myeloproliferative HE/HES, overlap HES, and idiopathic HES, and there are very little data to guide clinicians on treatment, particularly in the high proportion of patients who have a suboptimal response to corticosteroids (Klion, 2015). In this study, six of seven patients treated with peg-IFN alpha 2a had a sustained response and were able to discontinue corticosteroids. Interestingly, all of the patients experienced a decrease in the population of aberrant T-cells during therapy, and four had normalization of their T-cell immunophenotype, in contrast to previous reports wherein some patients demonstrated persistence or even an increase in the aberrant population on treatment (Khoury, 2017). Some experts recommend maintaining patients with L-HES receiving interferon on low dose steroids to mitigate the risk of transformation to T-cell lymphoma, although this is controversial (Klion, 2015). To date, none of the six patients in this study treated with peg-IFN alpha 2a in the absence of steroids have developed T-cell lymphoma. This case series provides further evidence for peg-IFN alpha 2a as an effective treatment option for steroid resistant or refractory patients with L-HES. This work was supported by the Hal Kettleson Hematology Research Fund

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