Systemic Mastocytosis with Eosinophilia: A Novel Diagnostic Approach To Distinguish Imatinib-Resistant Kit D816V-Associated Mast Cell Disease from Imatinib-Sensitive FIP1L1/PDGFRA-Associated Hypereosinophilic Syndrome.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2683-2683
Author(s):  
Todd M. Wilson ◽  
Irina Maric ◽  
Amy D. Klion ◽  
Cem Akin ◽  
Melody Carter ◽  
...  
Keyword(s):  
Risk Factor ◽  
Systemic Mastocytosis ◽  
Total Serum ◽  
Peripheral Eosinophilia ◽  
Serum Tryptase ◽  
Blood Eosinophilia ◽  
Cardiac Symptoms ◽  
Imatinib Resistant ◽  
Kit D816v ◽  
Peripheral Blood Eosinophilia

Abstract Systemic mastocytosis (SM) is a clonal myeloproliferative disease with variable clinical manifestations. The D816V mutation in the c-kit gene, present in over 90% of adult patients with SM, results in constitutive activation of the receptor tyrosine kinase and is believed to be related to disease pathogenesis. Although the majority of patients with SM lack peripheral blood eosinophilia, a subgroup exists and is classified as SM with eosinophilia (SM-eo). Recently, several reports of patients with SM-eo described the presence of either the Kit D816V mutation or the FIP1L1/PDGFRA fusion oncogene. Numerous similarities between patients with FIP1L1/PDGFRA and KIT D816V-associated peripheral blood eosinophilia have caused confusion about the management and specifically the role of imatinib in the treatment of these patients. It is of paramount importance to distinguish these two groups with pathologically similar, but molecularly and clinically distinct diseases. We thus compared the clinical, laboratory, and molecular features of 12 patients who met WHO criteria for SM (including presence of the D816V kit mutation) and had associated peripheral eosinophilia with those of 17 patients with peripheral eosinophilia and the FIP1L1/PDGFRA fusion oncogene (diagnosed with HES and evaluated at the same institution) and to the published reports of FIP1L1/PDGFRA-HES patients. Based on these comparisons, a number of clinical features appeared to be of potential use in distinguishing these two disorders. The presence of cardiac symptoms, a total serum tryptase under 60 ng/ml or the presence of either scattered mast cells or loose aggregates was found to be suggestive of FIP1L1/PDGFRA-associated disease. The presence of urticaria pigmentosa, a total serum tryptase over 150 ng/ml, the presence of dense mast cell aggregates and female sex were suggestive of Kit D816V-associated disease. To confirm and standardize this clinical classification, statistical methods were employed to test 21 possible risk factors for their ability to distinguish Kit and FIP1L1/PDGFRA-associated disease. Calculated risk factor scores were developed based on this analysis. Applying this risk factor based system, 16/17 FIP1L1/PDGFRA patients were classified correctly, with one patient neutral and all 12 Kit D816V SM-eo patients were classified correctly. Thirty four FIP1L1/PDGFRA patients in the literature were available for analysis, although all risk factors to create the score were not available for all patients. Despite this, 25/34 FIP1L1/PDGFRA patients were correctly predicted as FIP1L1/PDGFRA, 4/34 patients were neutral and 5/34 were misclassified as Kit D816V-associated SM-eo. These data suggest that the risk factor-based system presented in this study is useful in distinguishing imatinib-sensitive FIP1L1/PDGFRA-associated disease from imatinib-resistant Kit D816V-associated disease. Parameter SM-eo FIP1L1/PDGFRA HES Number patients 12 17 Male/Female 7/5 17/0 Cardiac symptoms 0/12 6/15 UP 7/12 0/15 Mean serum tryptase (ng/ml) 229 28 (n=13) Dense marrow aggregates 12/12 1/10

The Association of Skin Test Reactivity, Total Serum IgE Levels, and Peripheral Blood Eosinophilia with Asthma in Kuwait

2000 ◽  
Vol 37 (6) ◽  
pp. 481-488 ◽  
Author(s):  
Mousa Khadadah ◽  
B. O. Onadeko ◽  
C. I. Ezeamuzie ◽  
H. T. Mustafa ◽  
R. Marouf ◽  
...  
Keyword(s):  
Skin Test ◽  
Peripheral Blood ◽  
Total Serum ◽  
Skin Test Reactivity ◽  
Blood Eosinophilia ◽  
Serum Ige ◽  
Peripheral Blood Eosinophilia

Sorafenib Potently Inhibits ETV6-PDGFRβ and FLT3 Mutants, and Shows Activity Against FLT3 Mutants That Are Resistant to Other Small Molecule Inhibitors.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1993-1993
Author(s):  
Els Lierman ◽  
Idoya Lahortiga ◽  
Helen Van Miegroet ◽  
Nicole Mentens ◽  
Peter Marynen ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Small Molecule ◽  
Tyrosine Kinases ◽  
Systemic Mastocytosis ◽  
Imatinib Resistant ◽  
A Cell ◽  
Resistant Mutants ◽  
Cell Cycle Block ◽  
Myelomonocytic Leukemia ◽  
Kit D816v

Abstract Activated tyrosine kinases are implicated in the pathogenesis of chronic and acute leukemia, and represent attractive targets for therapy. Sorafenib (BAY43-9006, Nexavar®) is a small molecule B-RAF inhibitor that is used for the treatment of renal cell carcinoma. Sorafenib also has activity against receptor tyrosine kinases from the PDGFR and VEGFR families. Here we show that sorafenib is a potent inhibitor of the ETV6-PDGFRβ tyrosine kinase that is associated with chronic myelomonocytic leukemia. Oncogenic FLT3 receptor tyrosine kinase mutants implicated in the pathogenesis of acute myeloid leukemia are also potently inhibited by sorafenib, including some of the resistant mutants that confer resistance to PKC412 and other FLT3 inhibitors. Sorafenib induced a cell cycle block and apoptosis in the AML cell lines MV4-11 and MOLM-13, both expressing FLT3 with an internal tandem duplication. In contrast, the imatinib resistant KIT(D816V) mutant that is associated with systemic mastocytosis was found to be resistant to sorafenib. These results suggest that sorafenib could be used for the treatment of myeloid leukemias expressing activated forms of PDGFRβ, FLT3, and some PKC412 resistant mutants, but not for leukemias expressing imatinib resistant KIT(D816V).

scholarly journals State-of-the-Art on Biomarkers for Anaphylaxis in Obstetrics

Life ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 870
Author(s):  
Anca Angela Simionescu ◽  
Ana Maria Alexandra Stanescu ◽  
Florin-Dan Popescu
Keyword(s):  
High Risk ◽  
Pregnant Women ◽  
Systemic Mastocytosis ◽  
Interdisciplinary Approach ◽  
Medical Emergency ◽  
Total Serum ◽  
In Vitro Tests ◽  
Serum Tryptase

Anaphylaxis is an unpredictable systemic hypersensitivity reaction and constitutes a high risk of maternal and fetal morbidity and mortality when occurring during pregnancy. Currently, the acute management of anaphylaxis is based on clinical parameters. A total serum tryptase is only used to support an accurate diagnosis. There is a need to detect other biomarkers to further assess high-risk patients in obstetrics. Our objective is to present biomarkers in this complex interdisciplinary approach beyond obstetrician and anaesthetic management. Candidate biomarkers derive either from mediators involved in immunopathogenesis or upcoming molecules from systems biology and proteomics. Serum tryptase is determined by singleplex immunoassay method and is important in the evaluation of anaphylactic mast cell degranulation but also in the assessment of other risk factors for anaphylaxis such as systemic mastocytosis. Another category of biomarkers investigates the IgE-mediated sensitization to triggers potentially involved in the etiology of anaphylaxis in pregnant women, using singleplex or multiplex immunoassays. These in vitro tests with natural extracts from foods, venoms, latex or drugs, as well as with molecular allergen components, are useful because in vivo allergy tests cannot be performed on pregnant women in such a major medical emergency due to their additional potential risk of anaphylaxis.

Eosinophilic Neuritis and Eosinophilic Panniculitis in a Patient With Advanced Acquired Immunodeficiency Syndrome

2006 ◽  
Vol 130 (7) ◽  
pp. 1046-1048
Author(s):  
Anthony C. Soldano ◽  
Ruth Walters ◽  
Pamela A. Groben
Keyword(s):  
Human Immunodeficiency Virus ◽  
African American ◽  
Acquired Immunodeficiency Syndrome ◽  
Peripheral Eosinophilia ◽  
Blood Eosinophilia ◽  
Papular Eruption ◽  
Immunodeficiency Virus ◽  
Acquired Immunodeficiency ◽  
Immunodeficiency Syndrome ◽  
Peripheral Blood Eosinophilia

Abstract The pruritic, papular eruption of human immunodeficiency virus with associated peripheral eosinophilia is well documented. We describe a 32-year-old African American man with advanced acquired immunodeficiency syndrome; a generalized painful, pruritic, papular rash; peripheral blood eosinophilia; and perineural eosinophilic infiltrates with eosinophilic panniculitis. To our knowledge, the latter 2 features have not been previously described in the literature on human immunodeficiency virus dermatoses. We propose that eosinophilic neuritis and eosinophilic panniculitis may represent additional findings in the spectrum of cutaneous disease seen in patients with advanced acquired immunodeficiency syndrome.

Detection of c-Kit Mutation in Peripheral Blood vs. Bone Marrow Aspirates in Patients with Systemic Mastocytosis: Comparison Study of Pathological and Clinical Laboratory Findings in Patients with and without Detectable c-Kit Mutation in the Peripheral Blood.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3596-3596 ◽  
Author(s):  
Irina Maric ◽  
Jamie Robyn ◽  
Weiming Fu ◽  
Jennifer Stoddard ◽  
Dean D. Metcalfe ◽  
...  
Keyword(s):  
Mast Cells ◽  
Peripheral Blood ◽  
Mutational Analysis ◽  
Clinical Laboratory ◽  
Systemic Mastocytosis ◽  
Flow Cytometric Analysis ◽  
Serum Tryptase ◽  
Kit Mutation ◽  
Flow Cytometric ◽  
Kit D816v

Abstract The identification of the KIT D816V mutation in patients with systemic mastocytosis (SM) has lately gained a major prognostic significance, largely because of the availability of tyrosine kinase receptor inhibitors such as imatinib. Imatinib was shown to be ineffective in patients carrying KIT D816V mutation, but effective in cases with some other c-kit mutations. Therefore, it is of paramount importance to correctly identify SM patients with KIT D816V mutation. However, the reported frequency of the KIT D816V mutation in SM patients is highly variable in the literature (30%-over 95%). It has been suggested that such variability is due to patient selection, sensitivity of the molecular methods used to detect the mutation or the source of the tested specimen (peripheral blood (PB) vs. bone marrow (BM) aspirate). To date, there has been no systematic study comparing PB and BM mutational findings in SM patients. In this study, we performed mutational analysis of both PB and BM samples in SM patients and compared the results with pathological, clinical laboratory and flow cytometric findings in patients with and without a detectable c-kit mutation in PB. We analyzed in parallel BM aspirates and PB from 55 patients who came to our clinic for evaluation of SM. After diagnostic workup (physical evaluation, measurement of serum tryptase level, study of BM biopsy, flow cytometric analysis of mast cells and mutational analysis by RT-PCR/RFLP), 46 of 55 patients were diagnosed with SM using the WHO diagnostic criteria. Nine patients did not fulfill the WHO diagnostic criteria for SM and all tested negative for c-kit mutation. Out of 46 patients diagnosed with SM, all but two patients (44/46; 95.6%) tested positive for KIT D816V mutation in the BM aspirate, but only 9/46 patients (19.5%) had the mutation detectable in the PB. Two patients who tested negative for KIT D816V mutation in the BM were shown to carry different c-kit mutation by sequencing. No tested patients carried the FIP1L1-PDGFRa fusion gene. 42/46 patients (91%) fulfilled major WHO pathological criteria for diagnosis of SM (dense mast cell aggregates in the BM biopsy). The other 9% had increased atypical spindle-shaped mast cells in the BM biopsy without dense aggregates. Flow cytometric analysis of PB showed no significant increase in circulating mast cells in patients with a detectable KIT D816V mutation in PB (average less than 0.01% mast cells). Comparison of patients with and without a detectable PB mutation showed more extensive BM biopsy involvement by mast cells in PB positive patients (average 45% vs. 15%), higher average serum tryptase levels (266 ng/ml vs. 85 ng/ml) and higher average PB absolute eosinophil counts (710 vs. 234/uL). Flow cytometric analysis of BM mast cells showed that 100% of KIT D816V positive patients had aberrant CD25 expression on mast cells. CD2 expression was more variable, but comparable in both groups of patents (67% vs. 69%). We conclude that the source of the specimen for c-kit analysis is of crucial importance for correct diagnosis, and recommend that all patients with suspected SM should always have BM aspirates tested for the KIT D816V mutation. PB testing yields falsely negative results in over 80% of cases and identifies only SM patients with a markedly increased mast cell burden.

scholarly journals Hypereosinophilic Syndrome of Undetermined Significance – Difficulties in Clinical and Therapeutic Approach

2018 ◽  
Vol 15 (4) ◽  
pp. 61-65
Author(s):  
Vlad Florin Anton ◽  
Polliana Mihaela Leru
Keyword(s):  
Systemic Mastocytosis ◽  
Hypereosinophilic Syndrome ◽  
Genetic Mutation ◽  
High Serum ◽  
Parasitic Infections ◽  
High Dose ◽  
Serum Tryptase ◽  
Major Criterion ◽  
Kit D816v

AbstractWe report a case of a 69-year-old woman who is followed since seven years for persistent blood hypereosinophilia up to 5100/mmc. She has been extensively investigated for other diseases known to induce hypereosinophilia, including allergies, parasitic infections and neoplasia. No end-organ dysfunction could be confirmed. We considered a possible primary hypereosinophilic syndrome (HES) and determined the genetic mutation FIP1L1-PDGFRA characteristic for HES, which was negative.Bone marrow showed reactive eosinophilia with no malignant cells and rare mast cells, less than 15 in aggregates, which is the major criterion for diagnosing mastocytosis. Knowing the association between HES and mastocytosis, we measured and found high serum tryptase levels and positive c-kit D816V genetic mutation, characteristic for systemic mastocytosis. The patient was closely monitored, with regular hematologic and clinical evaluation, mainly for cardiac and neurologic manifestations.A short trial of high dose corticotherapy induced remission of hypereosinophilia, but this could not be maintained with lower doses. The clinical outcome during follow-up period was rather good, except mild cognitive decline and atrial fibrillation.The reported case is illustrative for versatile presentation and difficulties in management of hypereosinophilia in clinical practice.

The KIT D816V Allele Burden in Systemic Mastocytosis Is Strongly Associated with Disease Subtype.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2859-2859
Author(s):  
Juliana Schwaab ◽  
Philipp Erben ◽  
Hans-Peter Horny ◽  
Martina Teichmann ◽  
Georgia Metzgeroth ◽  
...  
Keyword(s):  
Mast Cell ◽  
Tyrosine Kinase ◽  
Detection Rate ◽  
Mutation Detection ◽  
Conflicts Of Interest ◽  
Systemic Mastocytosis ◽  
Serum Tryptase ◽  
Mutation Detection Rate ◽  
Allele Burden ◽  
Kit D816v

Abstract Abstract 2859 Point mutations in the kinase domain of the receptor tyrosine kinase KIT at position 816 (D816V >95%; D816H, D816Y, others <5%) play a central role in the pathogenesis, diagnosis and targeted treatment of systemic mastocytosis (SM). However, accurate numbers on the overall frequency of KIT D816V in the diverse SM subtypes remain largely unknown because of i) the rarity of disease, ii) highly variable mast cell burden in bone marrow (BM) and peripheral blood (PB) and iii) inadequate sensitivity of disparate assays. We therefore developed an allele-specific quantitative RT-PCR (RQ-PCR) with an enhanced sensitivity of 0.01–0.1% which was superior to D-HPLC (mutation detection rate: 0.5%-1%) or conventional sequencing (mutation detection rate: 10–20%). Classification of the patients into disease subtypes was performed according to the WHO 2008 classification. Irrespective of subtype, KIT D816 mutations were identified in 143/144 (99.3%) of patients (D816V, n=141, 98.6%; D816H, n=1; D816Y, n=1) with SM (indolent SM [ISM], n=62, 43.1%; smoldering SM [SSM], n=7, 4.9%; SM with associated hematological non-mast cell disease [SM-AHNMD], n=15, 10.4%, and aggressive SM/mast cell leukemia [ASM/MCL], n=59, 41%). As control groups, seven patients with cutaneous mastocytosis, 20 healthy individuals and 80 patients with chronic myeloid leukemia in molecular remission were negative for the KIT D816V mutation in BM and PB. All patients with SSM (n=7), SM-AHNMD (n=14) and ASM/MCL (n=56) were positive in BM and also in PB. In contrast, 25/51 (49%) ISM patients were positive in BM but negative in PB. The KIT D816V RQ-PCR was subsequently used for quantitative assessment of the KIT D816V allele burden, expressed as the ratio KIT D816V/total KIT, in a total of 207 samples from PB (n=126) and BM (n=81) of 141 KIT D816V positive patients. In BM, the median allele burden was 8.9% (range 1.1–48.3%) in ISM, 29.7% (range 13.6–39.4%, p=0.007) in SSM, 23.3% (range 1.8–45.8%, p=0.09) in SM-AHNMD and 30.7% (range 1–99%, p<0.0001) in ASM/MCL. In PB, the allele burden clearly allowed differentiation of ISM (median 0, range 0–15.2%) vs. SSM (median 8.8%, range 0.3–42.5%, p=0.001), ISM vs. SM-AHNMD (median 11.5%, range 0.2–64.9%, p<0.001) and ISM vs. ASM/MCL (median 33%, range 0.53–74.0%; p<0.001). The vast majority of ISM patients (47/51; 92%) had an allele burden in PB <10%. ISM patients with an allele burden ≥10% collectively showed overlapping symptoms of diarrhea with (n=2) or without (n=1) histologically confirmed bowel infiltration, mild cytopenia (n=1), splenomegaly (n=1) and/or abdominal lymphadenopathy (n=1) potentially indicating more advanced disease. The wide heterogeneity of the allele burden in SSM and SM-AHNMD patients reflects the clinical heterogeneity in these subtypes. Of interest, the correlation of clinical findings and allele burden also revealed that patients with ASM-CMML had a significantly higher allele burden than ASM patients without monocytosis (45.5% vs. 30.9%, p=0.0029). In order to evaluate the use of RQ-PCR for monitoring of residual disease, serial measurements of the allele burden in PB were performed in patients after chemotherapy with cladribine (n=1) or allogeneic stem cell transplantation (SCT, n=2). The patient on cladribine revealed a decrease from 42% to 5% within 9 months which was associated with a decrease of serum tryptase levels from 610 μg/l to 129 μg/l and a decrease of mast cells in BM from 70–80% to 10%. When the patient relapsed 18 months after completion of chemotherapy with progressive organomegaly and thrombocytopenia, the allele burden had also risen to 35%. In the two allografted patients, allele burden was 35% and 45%, respectively, prior to SCT. Both patients are currently in complete remission without detectable KIT D816V mutation 17 and 12 months after allogeneic SCT. We therefore conclude that the measurement of the KIT D816V allele burden in SM patients from cDNA is a useful complementary tool for diagnosis and subclassification of SM. In the new treatment era of successful use of tyrosine kinase inhibitors and allogeneic SCT, it may also become very useful for monitoring of response to treatment in addition to established parameters like C-findings, serum tryptase and BM histology. Disclosures: No relevant conflicts of interest to declare.

Unusual presentation of chronic eosinophilic pneumonia with mild peripheral eosinophilia

2021 ◽  
Vol 14 (2) ◽  
pp. e234914
Author(s):  
Rishikesh Meena ◽  
Abhishek Goyal ◽  
Shashwat Kirti Keshri ◽  
Alkesh Kumar Khurana
Keyword(s):  
Lung Diseases ◽  
Eosinophilic Pneumonia ◽  
Pulmonary Eosinophilia ◽  
Unknown Aetiology ◽  
Peripheral Eosinophilia ◽  
Blood Eosinophilia ◽  
Chronic Eosinophilic Pneumonia ◽  
Diffuse Parenchymal Lung Diseases ◽  
Peripheral Blood Eosinophilia ◽  
Parenchymal Lung

Chronic eosinophilic pneumonia (CEP) is a rare disorder of unknown aetiology which comes under the class of diffuse parenchymal lung diseases with eosinophilia. It is classically characterised by blood and pulmonary eosinophilia, peripheral consolidation on chest radiograph and prompt response to corticosteroid therapy. We report a case of CEP in a 66-year-old man, smoker showing bilateral pulmonary infiltrates with mild peripheral eosinophilia. Our study shows that CEP can be kept as a possibility if radiological pictures are consistent, even if peripheral blood eosinophilia is mild.

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