Phenotypic and genotypic characteristics of mastocytosis according to the age of onset.

International audienceAdult's mastocytosis is usually associated with persistent systemic involvement and c-kit 816 mutation, while pediatrics disease is mostly limited to the skin and often resolves spontaneously. We prospectively included 142 adult patients with histologically proven mastocytosis. We compared phenotypic and genotypic features of adults patients whose disease started during childhood (Group 1, n = 28) with those of patients whose disease started at adult's age (Group 2, n = 114). Genotypic analysis was performed on skin biopsy by sequencing of c-kit exons 17 and 8 to 13. According to WHO classification, the percentage of systemic disease was similar (75 vs. 73%) in 2 groups. C-kit 816 mutation was found in 42% and 77% of patients in groups 1 and 2, respectively (p<0.001). 816 c-kit mutation was associated with systemic mastocytosis in group 2 (87% of patients with systemic mastocytosis vs. 45% with cutaneous mastocytosis, p = 0.0001). Other c-kit activating mutations were found in 23% of patients with mastocytosis' onset before the age of 5, 0% between 6 and 15 years and 2% at adults' age (p<0.001). In conclusion, pathogenesis of mastocytosis significantly differs according to the age of disease's onset. Our data may have major therapeutic relevance when considering c-kit-targeted therapy

Response of a KIT-Positive Extra-Abdominal Fibromatosis to Imatinib Mesylate and KIT Genetic Analysis

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Phenotypic and Genotypic Characteristics of Mastocytosis Differ According to the Age of Disease’s Onset.

Abstract Mastocytosis is a heterogeneous group of disease with respect to clinical, biological and genotypic features, which may either occur during childhood or at the adult’s age. Adult’s mastocytosis is usually associated with persistent systemic involvement and c-kit 816 mutations, while pediatric’s disease is mostly limited to the skin and often resolves spontaneously during adolescence. No study has attended to compare characteristics of adult’s mastocytosis according to the age of disease’s onset. Among 155 adult patients with histologically proven cutaneous mastocytosis and complete phenotypic and genotypic data available recruited through the French mastocytosis network (AFIRMM), disease started before 15 years in 23 patients (15%) and later than 18 years in 132 patients (85%). We compared phenotypic and genotypic features of patients whose disease started during childhood (Group 1, n = 23) with those of 31 randomly allocated patients whose disease started at adult’s age (Group 2). Genotypic analysis was performed on skin biopsy by direct sequencing of c-kit exons 17 and 8 to 13 in which most of activating mutations are found. According to the WHO classification, the percentage of systemic disease was similar in both groups (61 vs. 79%) in groups 1 and 2, respectively. Bone pain (57% vs. 23%) and flush (83% vs. 39%) differ between groups (p &amp;lt; 0.01). Bullous lesions were only observed in group 1 (14%) while telangiectasia macularis eruptiva perstans was only observed in group 2 (16%). Major asthenia, syncope, mood disturbances, anaphylactoid reactions, gastrointestinal and respiratory disturbances and blood cell count, serum tryptase and liver enzymes levels did not differ between groups. C-kit 816 mutations was found in 33% and 77% of patients in groups 1 and 2, respectively (p &amp;lt; 0.001). 45% of patients whose disease’s onset occurred before the age of 2 years vs. 7% of those whose disease’s onset occurred later during childhood presented with C-kit 816 mutation (p &amp;lt; 0.001). Other c-kit activating mutations were found in 29% and 3% (p &amp;lt; 0.001) and lack of c-kit activating mutation in 38% and 20% (p &amp;lt; 0.001) in groups 1 and 2, respectively. In conclusion, pathogenesis of mastocytosis significantly differs according to the age of disease’s onset. Our data may have major therapeutic relevance when considering c-kit-targeted therapy.</jats:p

Lack of Detection of FIP1L1-PDGFRA Gene Fusion in a Cohort of Mastocytosis with Eosinophilia.

Abstract 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&amp;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 &amp;lt;15 ng/mm3), blood cell count, IgE levels (nl&amp;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.</jats:p

Efficacy and Safety of Cladribine in Adult Systemic Mastocytosis : A French Multicenter Study of 33 Patients.

Abstract Systemic mastocytosis (SM) is a myeloproliferative disabling disorder for which no consensual curative therapy is currently available. Recent preliminary experiences in small groups of patients using cladribine (2-CdA) were encouraging. We thus studied the efficacy and safety of 2-CdA in 33 patients enrolled in a compassionate program in France. Characteristics of patients were as follows: 19 male, 14 female, mean age 55y (17–76y), mean duration of disease 10 y (1m–71y). Treatment consisted in intravenous 2-CdA (1 to 6 cycles of 0.15 mg/kg/d administered in a 2-hour infusion or subcutaneously for 5 d, repeated at 4–12 weeks) for severe SM-related infiltration or symptoms. Patients were classified as having indolent SM (n=6), aggressive SM (n=22) or SM with an associated clonal hematologic non-MC-lineage (AHNMD) (n=4), mast cell leukemia (n=1). C-kit mutation analysis was performed in skin and/or bone marrow in 27 cases (D816V =24; WT=3). All failed previous symptomatic therapy and/or recombinant interferon-a (n=5). Evaluation was based according to consensus criteria (Valent et al. Leuk Research 2003). Major response, partial response and no response were observed in 24, 2, 7 patients, respectively. Mean time to best response was 4 months (1–12m), and mean duration of response was 16m (2–36). In responding patients skin lesions, hepatomegaly/ascitis, splenomegaly, bone involvement, peripheral blood cytopenia, major asthenia, flush, syncope/anaphylaxis, GI tract and pulmonary symptoms improved or disappeared. Treatment was overall well tolerated. Adverse events consisted mainly in peripheral blood cytopenia (n=10) with resolutive opportunistic infections in 2 patients. Although mast cell infiltration persisted in bone marrow, the patient with mast cell leukemia, responded to treatment with disappearance of circulating abnormal mast cells, and resolution of thrombocytopenia. Death was observed in 4 cases related to two disease progression and two acute myeloid leukemia. Therefore, as a single agent, cladribine is an effective and safe treatment in symptomatic and agressive SM. In contrast with interferon, cladribine may induce regression of mast cell tumoral burden. However, cladribine is ineffective to improve AHNMD. Further work is warranted to define the optimal regimen with respect to dose and schedule, and the usefulness of maintenance cladribine therapy.</jats:p

Characteristics of 142 adults with mastocytosis according to their age of onset.

<p>CM: cutaneous mastocytosis, ISM: indolent systemic mastocytosis, ASM: aggressive systemic mastocytosis, SSM: smouldering systemic matocytosis, SM-AHNMD: systemic mastocytosis with an associated haematological clonal non-mast cell lineage disease, TMPE: telangiectasia macularis eruptive perstans.</p

Primer positions are indicated from the c-Kit sequence published through the NCBI accession number X06182.

<p>Primer positions are indicated from the c-Kit sequence published through the NCBI accession number X06182.</p

Relationship between phenotype and genotype in patients with mastocytosis according to their age of onset.

<p>Data are expressed in number (percentage).</p