Hypereosinophilic Syndromes (HES)-Variable Presentation and Response to Current Treatment Options: Absence of the FIP1L1-PDGFRa Fusion Gene Does Not Exclude Imatinib as a Treatment Option.
Authors: Mitra Subir , Murphy Philip , Thornton Patrick , Mccloy Mary 
Published: April 2020

Background: Hypereosinophilic syndromes (HES) refers to a heterogenous group of disorders characterised by marked blood eosinophilia (&gt;1500/cu mm) and tissue eosinophilia (lasting for more than 6 months), in the absence of other eitiologies for eosinophilia, resulting in end organ damage. Eosinophilias may be a reactive condition or a chronic myeloproliferative disorder( with evidence of clonal proliferation). Reactive eosinophilias are due to release of cytokines(IL-3, IL-5, GM-CSF etc) and the common causes are parasitic (helminthic) infections, allergic diseases, vasculitides drug reactions and malignancies. Clonal eosinophilias are those in which the eosinophilia is a part of a clonal haematological malignancy, which is very often associated with the fusion gene FIP1L1-PDGFR alpha which causes the generation of a constitutively active Tyrosine Kinase. Several visceral complications like cardiomyopathies, nervous system involvement (eg paraparesis, cerebral infarction, eosinophilic meningitis etc) are often fatal illnesses. Treatment modalities for HES includes corticosteroids, chemotherapeutic agents(hydroxyurea, cyclophosphamide, vincristine) and alpha-interferon. Newer treatment modalities including tyrosine kinase inhibitors(eg Imatinib mesylate) and monoclonal anti-IL5 antibodies are now available. Patients carrying this fusion gene respond well to the Tyrosine Kinase Inhibitor, Imatinib. Some patients with HES, that are negative for this fusion gene, may also respond to Imatinib, suggesting that in such cases other Tyrosine Kinases may be dysregulated.

Aim: Retrospective review of the variable response of 7 patients with HES (over a period of 6 months), to current treatment modalities.

Methods: The 7 patients (6 Male, 1 Female; age range 37–80 yrs; mean age 56 yr) presented with eosinophilia in the range 2600–73,000/cumm. A response to treatment was defined as Eosinophil count&lt;1500/cumm or Eosinophil count &lt; 5% of the total leucocyte count in the peripheral blood. Four of the 7 patients received Imatinib as initial treatment. Two patient initially had steroids(Prednisolone/Methyl Prednisolone) followed by Imatinib and 1 patient (aged 80 yr) was treated with Hydroxyurea initially.

Results: Four of the six patients receiving Imatinib responded to it. Of the 2 patients not responding to Imatinib,1 responded partially to Hydroxyurea and the other did not respond to monotherapy with steroid or alpha-interferon(but eventually responded to a combination of steroids and alpha-interferon). The patient who had initial treatment with Hydroxyurea responded well. Of the 7 patients 1 was positive for the FIP1L1-PDGFRa fusion gene. One was equivocal, 3 were negative and 2 were not tested. Of the 2 that were negative 1 responded to Imatinib(see table).

Summary: Thus response of HES patients to the various treatment modalities is variable and often unpredictable. A trial of Imatinib is worth considering in all cases including the ones that are negative for the fusion gene, as they often respond.