Epidemiology, clinical picture and long-term outcomes of FIP1L1-PDGFRA-positive myeloid neoplasm with eosinophilia: Data from 151 patients.

FIP1L1-PDGFRA-positive myeloid neoplasm with eosinophilia (F/P+ MN-eo) is a rare disease: robust epidemiological data are lacking and reported issues are scarce, of low sample-size and limited follow-up. Imatinib mesylate (IM) is highly efficient but no predictive factor of relapse after discontinuation has yet been identified. One hundred and fifty-one patients with F/P+ MN-eo (143 males; mean age at diagnosis 49 years; mean annual incidence: 0.18 case per million population) were included in this retrospective nationwide study involving all French laboratories who perform the search of F/P fusion gene (study period: 2003-2019). The main organs involved included the spleen (44%), skin (32%), lungs (30%), heart (19%) and central nervous system (9%). Serum vitamin B12 and tryptase levels were elevated in 74/79 (94%) and 45/57 (79%) patients, respectively, and none of the 31 patients initially treated with corticosteroids achieved complete hematologic remission. All 148 (98%) IM-treated patients achieved complete hematologic and molecular (when tested, n = 84) responses. Forty-six patients eventually discontinued IM, among whom 20 (57%) relapsed. In multivariate analysis, time to IM initiation (continuous HR: 1,01 [0.99-1,03]; P = .05) and duration of IM treatment (continuous HR: 0,97 [0,95-0,99]; P = .004) were independent factors of relapse after discontinuation of IM. After a mean follow-up of 80 (56) months, the 1, 5- and 10-year overall survival rates in IM-treated patients were 99%, 95% and 84% respectively. In F/P+ MN-eo, prompt initiation of IM and longer treatment durations may prevent relapses after discontinuation of IM.

Surveying the serologic proteome in a tissue-specific kras(G12D) knockin mouse model of pancreatic cancer.

We have applied a serologic proteomic workflow involving three complementary MS approaches to a tissue-specific Kras(G12D) -knockin mouse model of pancreatic cancer that consistently forms precancerous lesions by 4 months of age. The three proteomics applications were highly complementary and allowed us to survey the entire range of low to high molecular weight serologic proteins. Combined, we identified 121 (49↓, 72↑) unique and statistically relevant serologic biomarkers with 88% previously reported to be associated with cancer and 38% specifically correlated with pancreatic cancer. Four markers, lysozyme C2, cytokeratin 19, Serpina1A and Pcf11, were further verified by Western blotting. When applying systems analysis, the top-associated gene ontology functions were tied to wound healing, RXR signaling, growth, differentiation and innate immune activation through the JAK/STAT pathway. Upon further investigation of the apparent immune response using a multiplex cytokine screen, we found that IFN-γ, VEGF and GM-CSF were significantly increased in serum from the Kras(G12D) animals compared to littermate controls. By combining three complementary MS applications, we were able to survey the native intact peptidome and the global proteome in parallel, unveiling pathways that may be biologically relevant to promotion of pancreatic cancer progression and serologic markers of noninvasive early-stage neoplasia.

[Myeloproliferative hypereosinophilic syndrome revealed by bipolar mucosal ulcerations]. / Syndrome hyperéosinophilique d'origine myéloproliférative révélé par des ulcérations muqueuses bipolaires.

BACKGROUND: Hypereosinophilic syndrome (HES) is defined as an eosinophil count equal to or greater than 1.5 G/L for more than 6 months with organ damage (heart, nervous system, lung, etc) after the exclusion of other common causes of eosinophilia. A myeloproliferative variant of HES with FIP1L1-PDGFRα fusion gene inducing constitutive activation of a tyrosine kinase receptor has been characterized. We report a case in which the diagnosis was revealed by mucosal erosions and ulcerations. PATIENTS AND METHODS: A 50-year-old man reported bipolar erosions. He presented with an erosion on the glans, an ulceration on the lower lip and mild dermographism. He had an eosinophil count of 7.5 G/L (n<0.7) and raised LDH at 520 IU/L (n<480). Screening for the usual causes of eosinophilia was negative. Histology of the labial ulceration showed a polymorphous inflammatory infiltrate containing eosinophils. A chest scan demonstrated a ground glass-like pulmonary infiltrate and broncho-alveolar lavage revealed eosinophilic alveolitis. The myelogram showed rich bone marrow with eosinophils. FIP1L1-PDGFRα fusion transcript was detected in the blood. Imatinib (Glivec(®)) was initiated and a favourable outcome was achieved within a few months and maintained after one year of treatment. DISCUSSION: Cutaneous signs are frequent features of HES. They are polymorphous and include pruritis, erythematous rash and urticaria. Mucosal ulcerations are uncommon and appear more frequently with the myeloproliferative FIP1L1-PDGFRα-associated variant of HES. Early diagnosis allows the onset of a targeted treatment with imatinib that may prevent the apparition of organ damage.

A single weekly dose of imatinib is sufficient to induce and maintain remission of chronic eosinophilic leukaemia in FIP1L1-PDGFRA-expressing patients.

Hypereosinophilic syndrome (HES) is defined as chronic, unexplained hypereosinophilia with organ involvement. A subset of HES patients presents an interstitial deletion in chromosome 4q12, which leads to the expression of an imatinib-responsive fusion gene, FIP1L1-PDGFRA. These patients are diagnosed as chronic eosinophilic leukaemia (CEL). We treated seven CEL and HES patients, six of which expressed FIP1L1-PDGFRA, with imatinib using initial daily doses ranging from 100 to 400 mg. In a remission maintenance phase, the patients were treated with imatinib once weekly. All imatinib-treated patients achieved a complete haematological remission (CHR), and five of the six patients with FIP1L1-PDGFRA expression exhibited molecular remission. The decreased imatinib doses were as follows: 200 mg/week in three patients, 100 mg/week in two patients and 100 mg/d in the remaining two patients. For remission maintenance, imatinib doses were set at 100 mg/week in five patients and 200 mg/week in two patients. At a median follow-up of 30 months all patients remained in CHR and FIP1L1-PDGFRA expression was undetectable in five of the six FIP1L1-PDGFRA-expressing patients. These data suggest that a single weekly dose of imatinib is sufficient to maintain remission in FIP1L1-PDGFRA- positive CEL patients.

Cell clonality in hypereosinophilic syndrome: what pathogenetic role?

OBJECTIVE: Idiopathic hypereosinophilic syndrome (HES) is a heterogeneous disorder, including either a myeloproliferative or a lymphoproliferative variant (l-HES). In l-HES, T-lymphocytes could be involved in the pathogenesis through several cytokines, including IL5. METHODS: We assayed both TCR Beta- and delta-rearrangements by fluorescent PCR, characterizing 14 patients affected by HES. Lyn activation (a src-kinase involved in the IL5 pathway) was also tested in 6 cases. RESULTS: FIP1L1-PDGFRa was detected in 4 cases (28.6%); a clonal TCR was found in 10 cases (71.4%), including cases FIP1L1-PDGFRalpha-positive; four cases did not show any molecular marker. In this series, levels of IL5, IL4, IL2 and gammaIFN were measured, without any significant difference among different subgroups. All pathological samples tested did not show Lyn activation. Immunophenotype was also characterized: only one case showed an atypical CD3-/CD4+ population in the bone marrow. CONCLUSION: This study would suggest that a real distinction between m- and l-HES is not wholly convincing and that clonal T-cell expansion could not be the "primum movens" but an epiphenomenon in HES.