Lack of Detection of FIP1L1-PDGFRA Gene Fusion in a Cohort of Mastocytosis with Eosinophilia.
Authors: Barete Stephane , Feger Frederic , Delabesse Eric , Lortholary Olivier , Casassus Philippe , Arock Michel , Palmerini Fabienne , Dubreuil Parice , de Gennes Christian , Frances Camille , Macintyre Elisabeth A. , Hermine Olivier 
Published: April 2020

Mastocytosis (MCD) is a heterogeneous disorder characterized by mast cells (MC) infiltration in various organs, mostly linked to Asp816Val c-kit mutation. Idiopathic hypereosinophilic syndrome (HES) as defined by Chusid et al criteria is linked to the expression of the FIP1LI-PDFRA fusion gene. An overlap between MCD with eosinophilia and HES may exist and in some instance FIP1LI-PDFRA HES with mast cells excess and high serum tryptase has been described as MCD variant with eosinophilia. Among a cohort of 250 MCD patients we analyzed clinical, biological, and genotypic data of 14 patients who had a sustained and elevated eosinophil count&gt; 700/mm3.Clinical data for MCD comprised symptoms related to MC infiltration and mediators release. Patients were classified following the Valent et al classification. Biological data referred to serum tryptase (nl &lt;15 ng/mm3), blood cell count, IgE levels (nl&lt; 200 UI). Cytopathology analysis of bone marrow. C-kit Asp816Val c-kit mutation was performed in involved skin and/or bone marrow. FIP1L1-PDGFRA fusion gene detection was performed in RNA of PBMCs and Bone marrow by PCR. Three control patients with HES without any criteria of SMCD were also investigated for FIP1L1-PDGFRA fusion gene. Fourteen patients with eosinophilia (Median 2305/mm3 (729–35000/mm3) were retrieved. Eosinophilia was detected before MCD for 7 cases (1 to 11 years), concomitantly for 6 cases and after for one case Patients characteristics were as follow: 8 females, 6 males, 56 ± 21 (18–76) years at MCD diagnosis, with flush (57%), shock (7%), urticaria pigmentosa (85%), gut involvement(74%), hepatosplenomegaly (43%), ascitis (36%), bone involvement (36%). All except two patients had systemic MCD (3 indolent, 5 aggressive, 3 associated with clonal haematological disorder (2 AMLs, 1CMML), 1 mast cell leukemia). Median serum tryptase value was a 100 ng/mm3. Haematological abnormalities were: thrombocytopenia (n=2), anemia (n=2), monocytosis (n=2). IgE levels were within normal value except for one patient with isolated cutaneous mastocytosis. Cytopathologic analysis showed mast cells in bone marrow except in two cases, and variable eosinophilic count infiltration (3 to 40%). Cytogenetic analysis found for two pts a 20q deletion and one monosomy 7. C-kit Asp816Val c-kit mutation was positive for all pts. FIP1L1-PDGFRA fusion gene detection was negative in all cases, but positive in the three HES. Four out six pts, treated for MCD with cladribine had a durable efficacy on eosinophilia count concomitantly to regression of MCD symptoms, whereas Interferon had no effect. 4 patients died as the consequence of the associated haematological disorders. In conclusion, Eosinophilia rarely occurs in MCD, but does so in all types of MCD. In contrast to HES it is not associated with FIP1L1-PDGFRA gene fusion but with D816V c-kit mutation. Therefore, it should not be treated with Glivec but with cladribine.