Chronic Eosinophilic Leukaemia (CEL) with FIP1L1-PDGFRalpha Rearrangement (F/P): The Response to Imatinib (IM) Is Durable. A Report of 33 Patients with A Follow –up of 30 to 92 Months.
Authors: Rondoni Michela , Ottaviani Emanuela , Cilloni Daniela , Piccaluga Pier Paolo , Paolini Stefania , Iacobucci Ilaria , Soverini Simona , Merante Serena , Messa Francesca , Buccisano Francesco , Tiribelli Mario , Pane Fabrizio , Saglio Giuseppe , Lauria Francesco , Baccarani Michele , Martinelli Giovanni 
Published: October 2019

Abstract
Abstract 3894
Poster Board III-830

Background
An interstitial deletion in the long arm of chromosome 4 leads to the formation of the fusion gene FIP1L1-PDGFRalpha (F/P) coding for a constitutively activated form of PDGFRalpha. The fusion gene represents a marker of CEL, and it predicts a dramatic response to imatinib mesylate (IM). Different F/P transcripts have been described, but the correlation with kinetic of molecular response to IM and with the clinical presentation is unknown. Remission duration is also still undefined.

Aim
The aim of this study was to evaluate the duration of IM response in F/P positive (F/P+) CEL patients and the correlation between their clinical behaviour and molecular characteristics of the transcripts.

Design and methods
A prospective phase 2 multicentre study of the use of IM 400 mg/daily in patients with hypereosinophilic syndrome, independently of F/P status was established in 2001. Hypereosinophilic syndrome was defined according to Chusid criteria (Blood, 1994; 83: 2759-2779). The presence of F/P transcript was investigated on bone marrow cells using a nested reverse transcriptase polymerase chain reaction (RT-PCR), as reported by Cools J (N Engl J Med. 2003; 348:1199-200). The samples were also purified and sequenced using the Big Dye Terminator Cycle Sequencing Kit (Applied Biosystems). Patients at diagnosis were systematically screened for organ damage with instrumental evaluation (chest radiography, echocardiogram, abdomen ultrasonography) and for the presence of symptoms. 72 patients were treated with IM 100 to 400 mg daily; the 33 F/P+ were monitored every three months for two years then every six months using nested RT-PCR. We will present the result of the 33 F/P+ patients.

Results
Median follow-up was of 51 months (range 30-92 months). There were 32 males and one female patients. Organ involvement was recorded in 42% of patients, with notably no skin involvement, splenomegaly reported in 7, cardiac involvement in 5, and in 2 cases the peculiar site of localization of soft tissue. After imatinib therapy all patients achieved a complete hematologic response (CHR) in less than one month, and PCR negativity in a median time of 3 months (range 1-9). They became negative for organ localizations and free of symptoms. No patient experienced cardiac failure. All patients who continue imatinib therapy remained in CHR and RT-PCR negative, with a dose of 100 to 400 mg daily. From September 2007 all patients except one (late responder) were treated with 100 mg daily. In six patients IM treatment was discontinued for variable period for different reasons, and in 5 cases the fusion transcript became rapidly detectable; CHR was maintained, other than in one case and the transcript was again undetectable upon treatment resumption, other than in one case. Twenty-eight samples were evaluable for sequencing. Molecular analysis demonstrate an extreme variability of FIP1L1-PDGFRA junction sequences, with FIP1L1 breackpoints scattered between exon 9 to 18, with several splicing variants, whereas all breackpoints in PDGFRA are located within exon 12. Fusion gene sequencing demonstrate an extreme variability, with lack of whole exons of FIP1L1, deletion of exons, with the presence of introns in a minority of cases. Region of FIP1L1 varies in length from 109 to more than 500 nucleotides. Transcript of the only female patient is the same of one of the males. No evidence of correlation was noted with kinetic of molecular response or with the presence at diagnosis of peculiar organ involvement. More complexity of transcript is noted in patients with longer history of disease prior to imatinib therapy.

Interpretation and conclusion
with this large series of patients we can confirm that the response to imatinib therapy is durable, is not influenced by the biologic features, but depends on continuous therapy. More complexity and variability in FIP1L1-PDGFRalpha transcripts does not lead to differences in terms of response to the therapy or phenotype of disease at diagnosis.

Disclosures:
Pane: Novartis: Research Funding; Ministero dell'Università/PRIN: Research Funding; Regione Campania: Research Funding; Ministero della Salute/Progetto integrato Oncologia: Research Funding. Saglio:Novartis: Honoraria; Celgene: Honoraria. Baccarani:Novartis Pharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Mayer Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau.