Long‐term remission of lymphocytic hypereosinophilic syndrome with imatinib mesylate

Abstract

A 66-year-old female patient was referred to us because of eosinophilia (1.6 × 109/L to 2.9 × 109/L) and a history of atopia including allergic rhinitis, chronic cough, and severe urticaria. She had experienced corticosteroid-related severe myopathy and adrenal deficiency. After excluding secondary causes and hematological malignancies, she underwent a colon biopsy, which showed submucosal inflammatory infiltrates including medium number of eosinophils. Karyotype was normal and RT-PCR was negative for the FIP1L1/PDGFRA transcript, TEL/PDGFRB, and BCR/ABL. By contrast, FACS analysis of bone marrow lymphocytes revealed a clonal but phenotypically normal CD4+ cell population with prevalence of the Vbeta 13.1 (Fig. 1A). Biopsy of a mildly enlarged axillary lymph node showed a polyclonal TCR pattern (Fig. 1C). Subsequently, a diagnosis of lymphocytic hypereosinophilic syndrome (l-HES) was made. Because of previous side effects, we decided to offer her a trial of imatinib mesylate [1-3]. She was started at 100 mg/day that was gradually increased to 400 mg. Eosinophils decreased by 50% by the seventh day and finally came down to 0.42 × 109/L after 4 months on therapy. She manifested no adverse events and eosinophil count ranged from 0.36 to 0.47 × 109/L during therapy, which has now reached 2 years. She remained free of symptoms apart from a seasonal allergic rhinitis boost. Nevertheless, on the 2-year hallmark, we found persistence of the TCR clone by flow cytometry (Fig. 1B) and no change of the colonic eosinophilic infiltrate. FACS analysis of bone marrow lymphocytes showing a clonal population of CD4+ lymphocytes at similar pretreatment (A) and post-treatment levels (B). The same Vbeta subset was polyclonal in the lymph node cells (C). Idiopathic HES is characterized by persistent blood eosinophilia (≥1.5 × 109/L) and eosinophil-related end-organ damage, with no recognized cause. Lymphocytic variant of HES is due to the increased expression of IL-5 by aberrant or clonal T-lymphocyte populations. The predominant immunophenotypic finding is an aberrant CD3-CD4+ T-cell subset [4]. Demonstration of T-cell clonality by flow cytometry of by PCR was considered adequate for l-HES designation, although this has been disputed by the finding of a large proportion (43%) of patients with idiopathic HES bearing T-cell clones by PCR [5]. The flow cytometry method has the advantage of being quantitative and more specific. A prominent clonal expansion in the CD4 + subset may well exclude an incidental finding [6]. Our patient did not have any change in the TCR clone after achieving hematological remission, which excludes a secondary phenomenon [7]. There is no clear data regarding the efficacy of various I-HES therapies. Corticosteroids may not lower the aberrant T-cell population and interferon-alpha may exhibit an anti-apoptotic effect on clonal CD3-CD4+ cells [8]. Anti-IL-5 antibody and alemtuzumab could prove more successful [9]. On the other hand, imatinib mesylate is considered the golden standard in FIP1L1-PDGFRA-positive patients. A few patients without any known PDGFR mutations have responded to imatinib [1, 3]. Higher doses are generally required and the response, if noted, is usually slow [3, 10] and short lived, in contrast to our patient who has now reached 24 months of continuous remission [11]. To our knowledge, our patient represents the first extensively studied case of l-HES with response to imatinib, which shows the possibility of a long-term remission and raises questions about a possible mechanism. The large size of the clone (65%) in our patient and its CD4+ restriction underlines a significant pathogenetic association. A common molecular defect originating in the stem cell does not seem probable because of the persistence of the T-cell clone post remission. Another deregulated kinase could be responsible. Imatinib is not known to interfere with IL-5 signaling, but eosinophils express a functional c-kit receptor, which is a known target of imatinib [12]. This case underlines the need for a better elucidation of the relationship between the presence of a T-cell clone and hypereosinophilia. There is yet no proof that a cytoreductive approach against T-cells is mandatory, especially in the case of a clonal but not otherwise aberrant or cytogenetically abnormal T-cell population, which might place a higher risk of transformation. In this context or when first line therapy confers to significant morbidity, a trial of imatinib can be worthy. Anna Christoforidou*, Ioannis Kotsianidis*, Dimitrios Margaritis*, Athanasios Anastasiadis*, Eudoxia Douvali*, Costas Tsatalas*, * Department of Hematology, University Hospital of Alexandroupolis Alexandroupolis, Greece.