A Phase-II-Study To Evaluate Efficacy and Safety of Imatinib in Eosinophilia-Associated Myeloproliferative Disorders and Idiopathic Hypereosinophilic Syndrome.
Authors: Metzgeroth Georgia , Popp Helena , Walz Christoph , Erben Philipp , Mix Jürgen , Müller Martin C. , Hehlmann Rüdiger , Hochhaus Andreas , Reiter Andreas 
Published: April 2020

Abstract
Eosinophilia is a common clinical finding which is associated with a large number of highly variable non-clonal and clonal disorders. An idiopathic hypereosinophilic syndrome (HES) is diagnosed when the blood eosinophil count is persistently greater than 1500/μl for at least 6 months (mo), which is neither clonal nor reactive and which causes damage to end organs such as heart, skin or nervous system. Clonal eosinophilia is most frequently found in association with myeloproliferative disorders (EosMPD) where clonality is usually demonstrated by cytogenetic abnormalities and/or the presence of fusion genes with involvement of PDGFRA, PDGFRB, FGFR1 or JAK2. Treatment options for patients (pts) with EosMPD and HES include corticosteroids, chemotherapy, interferon-α and more recently imatinib.We therefore initiated a phase-II-study for the treatment of EosMPD (n=21) with rearrangement of PDGFRA (FIP1L1-PDGFRA fusion gene, n=17) or PDGFRB (variable fusion genes, n=4) and HES (no specific marker, n=14). Median age at diagnosis was 52 years (range, 20–72). The overall male/female ratio was 3.4:1 with a significant male predominance in EosMPD (19/21 pts, 90%). Pts received imatinib at doses ranging between 100 and 400 mg/d according to the type of the underlying fusion gene, tolerability and response to treatment. Median time of treatment has been 7 mo (range, 1–22). In FIP1L1-PDGFRA positive pts, complete hematological remission (CHR) was achieved within 1 or 3 mo in 59% (10/17) and 100% (15/15) of pts, respectively. Complete molecular remission (CMR) defined as a negative nested RT-PCR for FIP1L1-PDGFRA fusion transcripts in peripheral blood, was seen within 3 or 6 mo in 27% (4/15) and 83% (10/12) of pts, respectively. All four pts with PDGFRB fusion genes were treated with 400 mg/d imatinib and achieved a CHR after a median time of 1.4 mo (range 0.5–2), one of them achieved a CMR. No relapses have yet been observed in imatinib-treated EosMPD. All HES pts have been treated with 400 mg/d imatinib. Partial or complete clinical and hematological responses have been observed in 6 of 14 pts (43%) which were transient in 3 pts (median 6 mo, range, 4–6). Three of 14 pts (21%) are in sustained remission in a median period of 21 mo (range, 18–21) after start of imatinib. Overall, imatinib was well tolerated with toxicities only of WHO grade I and II, predominantly oedema (n=6), rash (n=5) and nausea (n=3). We conclude that pts who present with sustained non-reactive eosinophilia should be analysed for the presence of the FIP1L1-PDGFRA fusion gene. Cytogenetic analysis is recommended in FIP1L1-PDGFRA negative cases in order to exclude rearrangements of genes coding for imatinib-sensitive (PDGFRA, PDGFRB) or imatinib-resistant (JAK2, FGFR1) tyrosine kinases. Imatinib seems to be less effective in HES without specific marker. Further studies are warranted to find out optimal dose and duration of treatment with imatinib in responding pts with EosMPD and HES.