Imatinib Mesylate Can Induce Molecular Complete Remission in Idiopathic Hypereosinophilic Syndrome (HES). A Phase II Multicentric Italian Clinical Trial.
Authors: Martinelli Giovanni , Cilloni Daniela , Rondoni Michela , Messa Francesca , Ottaviani Emanuela , Gottardi Enrico , Piccaluga Pier Paolo , Malagola Michele , Soverini Simona , Merante Serena , Alimena Giuliana , Bosi Costanza , De Vivo Antonio , Rosti Gianantonio , Giugliano Emilia , Pane Fabrizio , Izzo Barbara , Testoni Nicoletta , Paolini Stefania , Rancati Francesca , Bassan Renato , Mecucci Cristina , Baccarani Michele , Saglio Giuseppe 
Published: April 2020

Abstract
Idiopathic hyper-eosinophilic syndrome (HES) is a rare haematological disorder characterized by persistent peripheral blood greater than 1,500 cells/μL lasting for more than 6 months, in the absence of other apparent aetiologies for eosinophilia with signs and symptoms of organ involvement. HES may be a reactive condition or a chronic myeloproliferative disorder with evidence of clonal proliferation, in which latter case it is usually referred to as chronic eosinophilic leukemia (CEL). Patients with HES generally have a poor prognosis, but the course of the disease may be variable. Severe visceral complications, including cardiopathies, are common and are often fatal illness. Treatment of HES includes corticosteroids, chemotherapeutic agents (such as cyclophosphamide, vincristine, and hydroxyurea), and, more recently, interferon-alpha (IFN-alpha).
Recently, Cools et al. reported the involvement of PDGFRA, fused with FIP1L1, in a number of HES patients responsive to imatinib therapy. We treated with imatinib mesylate (100 to 400 mg daily) 59 patients affected by Hyper-Eosinophilic Syndrome (HES) enrolled in a multicentric Italian phase 2 clinical trial. All the patients were studied by molecular analysis for expression of FIP1L1-PDGFRA, TEL-PDGFRB, FGFR1-BCR and BCR-ABL chimerical transcripts. 32 patients (45%) were positive for the FIP1L1-PDGFRA rearrangement. Rapid, haematological complete responses (HCR) were recorded after one month of therapy in all FIP1L1-PDGFRA positive. In 36 patients resulted negative for FIP1L1-PDGFRA rearrangement we observed 8 (22%) hematological improvement (HI) and one HCR (HI+HCR 25%). Furthermore, a molecular complete remission (defined as the disappearance of FIP1L1-PDGFRA at qualitative RT-PCR evaluation) was recorded in 13 (68%) patients of the 19 valuable after three months of therapy, and all but one (94%) patients resulted negative for the presence of the rearrangement after six months of therapy. No significant toxicity was seen during the treatment. The median follow up was 4 months (range: 2–39). This is the largest series of HES patients treated with Imatinib with strong evidence of hematological and molecular effectiveness and absence of long term significant toxicity.
This phase II study supports the use of Imatinib as first line therapy in FIP1L1-PDGFRA rearrangements positive HES patients. Acknowledgments: COFIN 2003, by FIRB 2001, by the University of Bologna (60%), by the Italian Association for Cancer Research (A.I.R.C.), by the Italian National Research Council (C.N.R), by Fondazione Del Monte of Bologna and Ravenna (Italy), A.I.L. grants, European LeukemiaNet grants.