Hypereosinophilic syndromes in the precision medicine era: clinical, molecular aspects and therapeutic approaches (targeted therapies)

ABSTRACT

Introduction: Hypereosinophilic syndromes are a heterogeneous group of disorders that may be associated with life-threatening organ injury as a result of tissues infiltration by eosinophils. The main goal of therapy is to mitigate eosinophil-mediated organ damage. When possible, therapy should be directed at the underlying etiology. However, even in the absence of any known cause, when organ damage is present, hypereosinophilia must be treated promptly and aggressively to reduce potential morbidity and mortality.

Areas covered: Conventional therapies, including corticosteroids, hydroxyurea (hydroxycarbamide) and interferon-alpha, have shown variable efficacy and a non-negligible toxicity emphasizing the need of new therapeutic strategies based on drugs with different mechanisms of action.

Expert opinion: Tyrosine kinase inhibitors have a central role among targeted therapies of hypereosinophilic syndromes. Imatinib, initially empirically used based on its activity in chronic myeloid leukemia, achieved preliminary excellent results further confirmed in large series of patients. Third-generation tyrosine kinase inhibitors such as ponatinib, while active in vitro and in vivo in animals, still deserve confirmation in properly designed clinical trials. In addition, clinical investigation on monoclonal antibodies against interleukin-5, interleukin-5Rα, IgE, and CD52 represents a promising area of research.

KEYWORDS:

• Hypereosinophilic syndromes
• chronic eosinophilic leukemia
• not otherwise specified
• PDGFRA
• PDGFRB
• FGFR1
• imatinib
• mepolizumab
• benralizumab
• alemtuzumab

Article highlights

• Hypereosinophilic syndromes are a heterogeneous group of disorders characterized by hypereosinophilia, which may be associated with life-threatening organ damage;

• In the new 2016 WHO revision it was endorsed a subtypes classification according to the molecular profile including 1) myeloproliferative neoplasm subtype: chronic eosinophilic leukemia, not otherwise specified; 2) myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB, or FGFR1 or with PCM1-JAK2; and 3) idiopathic HES;

• Diagnostic evaluation of primary hypereosinophilia relies on a combination of morphologic evaluation of both peripheral blood and bone marrow, serum chemistry, standard cytogenetic techniques, FISH, flow immunocytometry to detect histopathologic or molecular evidence for an acute or chronic myeloid or lymphoid malignancy;

• The goal of therapy is to mitigate eosinophil-mediated organ damage. When possible, therapy should be directed at the underlying etiology. However, even in the absence of any known cause, when organ damage is present, hypereosinophilia must be treated promptly and aggressively to reduce potential morbidity and mortality;

• For idiopathic HES and CEL, NOS patients the first-line treatment should be represented by corticosteroids or hydroxyurea (hydroxycarbamide)/IFN-alpha, respectively; in case of resistance/intolerance, participation into a clinical trial should always be considered;

• The initial use of TKIs was empirically based on common features with other myeloid disorders and, excellent results were reported in early investigations on small series of patients;

• Currently, imatinib is the only TKI approved for HES treatment as it represents the drug of choice for the so-called myeloid neoplasms with eosinophilia and PDGFRA rearrangement at a lower dosage than that used for chronic myeloid leukemia, typically as low as 100 mg daily, but also for those forms with PDFGRB rearrangement at the standard dosage;

• In recent years, some FDA-approved JAK inhibitors have been tried in HES, especially in those cases associated with gain-of-function mutations involving the JAK/STAT signaling pathway, showing promising results;

• Anti-IL-5 and anti-IL-5Rα antibody approaches have been studied in HES based on the cytokine’s role as a differentiation, activation, and survival factor for eosinophils, including mepolizumab, reslizumab, and benralizumab, which shows great potential for being efficacious in HES;

• Several new biologics and tyrosine kinase inhibitors have been shown to lower eosinophil numbers, but more clinical trials are needed to confirm efficacy in HES.

Declaration of interest

A Iurlo has received speaker honoraria from Novartis, Pfizer, and Incyte. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or conflict with the subject matter or materials discussed in this manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.